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BIO3041 medchem > medchem > Flashcards

medchem Flashcards

1
Q

how is polarisation of a neuron created and how does depolarisation occur

A

the natural eqm flow of potassium ions out of the cell creates a electric potential across the neuron cell membrane = polarisation.
depolarisation occurs when certain neurotransmitters bind to post-synaptic cell and open the sodium ion channels.
sodium ions flow -> cell and the internal electric potential becomes less negative and results in stimulation of the neuron.

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2
Q

why is ACE2 an important enzyme in humans

A

ACE-2 is membrane-bound enzyme with a homeostatic role. Present in most organs; including airway epithelial cells and vascular endothelial cells.

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3
Q

describe the actions of voltage-gated sodium and potassium ion channels in the axon leading to an action potential

A

they are controlled by the electric potential of the cell membrane.
when the post-synaptic cell body is depolarised, the sodium ion channels of the axon open also.
the stronger the cell body depolarisation, the more sodium channels open and the likelihood of reaching the threshold to generate a signal increases.

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4
Q

infection phase of HIV life cycle

A

HIV surface proteins gp120 and gp41 and T-cell surface proteins CD4, CCR5 and CXCR4 are crucial

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5
Q

integration phase of HIV life cycle

A

Integration into T-cell DNA: HIV capsid disintegrates (viral protease); viral RNA converted into proviral DNA by viral reverse transcriptase; proviral DNA incorporated into host DNA by viral integrase

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6
Q

release phase of HIV life cycle

A

New gp120 and gp 41 incorporate into cell membrane, other viral proteins and RNA congregate on inner membrane surface; budding occurs to release new viruses

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7
Q

processing phase of HIV life cycle

A

Transcription produces more viral RNA, some is incorporated into new virions, some translated into viral proteins

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8
Q

ADME

A

Absorption, Distribution Metabolism, Excretion

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9
Q

what happens if an oral drug is too lipophilic

A

instead of crossing through membranes drug will become stuck in fat tissue

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10
Q

what happens if an oral drug is too polar

A

it will be excreted by kidneys

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11
Q

what happens if an oral drug is too anionic or cationic

A

too cationic = bind nucleic acids
too anionic = bind plasma proteins

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12
Q

requirements for orally administrated drug

A
  • water soluble to dissolve in GI tract & blood
  • lipophilic to cross membranes/BBB
  • resistant to stomach acid & enzymes
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13
Q

3 measurable parameters of pharmacokinetics

A

plasma concentration
half-life
rate constants

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14
Q

generally, how are drugs metabolized?

A

via various routes, enzyme controlled reactions that convert drugs into biologically inert metabolites that are easily excreted
Phase I and Phase 2

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15
Q

Phase 1 metabolism

A

-introduce or reveal functional groups important in Phase 2
-products are more water soluble than original drug

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16
Q

what makes a drug more excretable?

A

increased water solubility
i.e. polarity

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17
Q

Phase 2 metabolism

A

-products much more water soluble than original drug
-products form bulk of inactive excreted metabolites

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18
Q

methods to study drug metabolism

A

-radiolabeling the drug
-chromatography (mainly HPLC)
-NMR and/or MS

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19
Q

biological factors affecting drug metabolism

A

-dose level
-route of administration
-species differences
-sex
-age
-disease
-other drugs
-genetics

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20
Q

why does dose level matter when designing drugs?

A

dose level increasing will saturate enzyme capability leading to alternative pathways & toxic products

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21
Q

why does route of administration matter when designing drugs?

A

the concentration of effective drug decreases if drug is metabolized in organs before reaching circulation

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22
Q

why does variation between species matter when designing drugs?

A

rates, dose etc may be different between model organism & human
sex of rats is important for drug efficacy but not in humans unless pregnant

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23
Q

why does age matter when designing drugs?

A

liver function decreases with age

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24
Q

why does disease matter when designing drugs?

A

liver disease has greatest effect

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25
Q

why do other drugs matter when designing drugs?

A

one drug can affect the metabolism of another

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26
Q

why does genetics matter when designing drugs?

A

isoenzymes

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27
Q

drug metabolism occurs in…

A

all tissues and most biological fluids
most reactions occur in liver
selective reactions can occur in kidneys, lungs, brain, placenta

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28
Q

6 main types of Phase 1 metabolic reactions

A

Oxidation
Reduction
Hydrolyses
Hyrdations
Deacteylations
Isomerisations

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29
Q

3 main types Phase 2 metabolic reactions

A

acylation
sulfate formation
conjugation
–mainly occur in liver and gut wall

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30
Q

How to increase resistance to metabolism?

A

steric shields
bioisosteres (electronic effect)
combination of the 2 ^
metabolic blockers

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31
Q

how & why may it be necessary to decrease lifetime of a drug?

A

too resistant to metabolism
add metabolically labile groups

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32
Q

what is a prodrug

A

biologically inert but converted to an active drug in the body after metabolism

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33
Q

what group could be added to reduce lifetime of drug?

A

CH3 is readily oxidized > CH2OH and CO2H

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34
Q

6 benefits of prodrugs

A

improve membrane permeability
prolong drug activity
mask toxicity
increase/decrease water solubility
target tumors (selectivity by only being activated inside tumor)

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35
Q

how can you sterically shield a drug? example

A

e.g. tertiary butyl group
a big bulky group that prevents enzyme from accessing it’s target functional group

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36
Q

how can you metabolically block metabolism of a drug to increase lifetime?

A

adding a functional group to block site of metabolism on the drug

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37
Q

what functional groups can you add to improve membrane permeability?

A

hydrophobic groups
e.g. (long) alkyl chains

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38
Q

what functional groups can you add to prolong drug activity?

A

fatty side chain will embed prodrug in membrane and guarantees slow release into blood where it is rapidly hydrolyzed

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39
Q

how can you mask drug toxicity?

A

add functional group that slows release of high dose
prevents saturation of metabolic enzymes which decreases side effects caused by alternate metabolism

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40
Q

what kind of functional group should be added to increase water solubility of a drug?

A

polar/hydrophilic
e.g. lysine ester

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41
Q

what is the most common functional group added to decrease water solubility?

A

most examples involve esters

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42
Q

what is ADEPT

A

antibody directed enzyme prodrug therapy

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43
Q

antitumor mechanism of prodrug indolequinone

A

metabolized inside cancer cell to active form by NQO1
becomes a powerful electrophile which intercalates and irreversibly alkylates DNA

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44
Q

what is GDEPT

A

gene directed enzyme prodrug therapy

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45
Q

functional groups most prone to Phase 1 oxidation

A

N-methyl
aromatic rings
terminus of alkyl chains
least hinderered position of acicyclic ring

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46
Q

functional groups most prone to Phase 1 reduction by reductases

A

nitro
azo
carbonyl

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47
Q

functional group most prone to Phase 1 hydrolysis by esterases

A

ester

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48
Q

functional group most prone to Phase 1 hydrolysis by peptidases

A

amides

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49
Q

how do cytochrome P450 enzymes oxidise a drug

A

split molecular oxygen
add O to C, N, P or S atom
H2O and NADP+ produced
requires NADPH and H+

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50
Q

the most likely C atoms to be oxidised in Phase 1 are

A

exposed or activated

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51
Q

oxidation of saturated carbon centres produce what functional groups

A

epoxide

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52
Q

lipinski’s rule of 5

A

-HBD < 5
-HBA < 10
-MW < 500 d
-(Clog P) < 5

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53
Q

pharmacophore

A

the important functional groups required for activity and their relative positions in space.

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54
Q

hydrophobicity

A

hydrophobic character important for crossing biological membranes & receptor interactions

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55
Q

eqn partition coefficient

A

[drug] in octanol/ [drug] in aqueous solution

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56
Q

hydrophobic compounds have _ partition coefficient

A

high

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57
Q

polar surface area

A

surface associated with heteroatoms & polar H atoms

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58
Q

exceptions to Lipinksi’s rule

A

Antibiotics, antifungals, vitamins and cardiac glycosides
act as substrates for naturally occurring transporters
natural products
drugs not required to be orally bioavailable

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59
Q

types of minor changes to determine SAR

A

the size and shape of the carbon skeleton
the nature and degree of substitution
the stereochemistry of the lead

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60
Q

SAR approach

A

attempts to remove element of luck from drug design by establishing mathematical relationship:
eqn between biological activity and measurable physicochemical parameters.

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61
Q

IC50

A

concentration required to achieve 50% inhibition

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62
Q

ED50

A

mean effective dose required to produce a therapeutic effect in 50% of test sample

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63
Q

main properties of a drug that influence its activity are

A

Lipophilicity
Electronic effects within the molecule
Size and shape of the molecule

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64
Q

eqn: relationship between P and drug activity

A

log(1/C) = K1log(P) + K2
y= mx + c

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65
Q

increasing hydrophobicity does not directly translate to biological activity because…

A

a drug can be so hydrophobic it gets trapped in fat deposits

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66
Q

eqn: Hansch parabolic relationship

A

log(1/C) = K1log(P)^2 + K2logP + K3

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67
Q

optimisation of lead compound: vary accessible substituents

A

variation of alkyl group i.e. length

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68
Q

optimisation of lead compound: increase activity and/or decrease side effects

A

increase rigidity i.e. add ring or double/triple bond to inhibit bond rotation

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69
Q

optimisation of lead compound: simplify synthesis

A

strip away non-essential regions after SAR

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70
Q

optimisation of lead compound: increase selectivity and/or activity

A

ring fusion

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71
Q

optimisation of lead compound: add additional binding group

A

aromatic ring > heteroaromatic ring
heteroaromatic ring > different heteroaromatic ring (different ring size or position of heteroatom)

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72
Q

optimisation of lead compound: make use of unused (extra) binding pocket

A

extending the structure

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73
Q

optimisation of lead compound: confer selectivity

A

varying bulk (increasing may confer specificity to a receptor with larger binding pocket, and rule out binding to a receptor with a smaller binding pocket)

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74
Q

bioisosteres for -OH

A

-NHCOR
-NHSO(2)R
-CH(2)OH
-NHCONH(2)
-NHCN
-CHCN(2)

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75
Q

bioisosteres for halogens

A

-CF(3)
-CN
-NCN(2)
-CCN(3)

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76
Q

bioisosteres of thiourea

A

-NHC(=S)-NH(2)
-NHC(=NCN)NH(2)
-NHC(=CHNO(2))NH(2)

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77
Q

11 optimisations of a lead compound

A
  • vary alkyl substituents
  • increase bulk/chain length (hydrophobic interactions)
  • vary bulk (selectivity)
  • extension of structure (unused binding region)
  • ring expansion/contraction
  • ring variation (heteroatoms etc.)
  • ring fusions
  • simplification
  • rigidification
  • conformation blockers
  • isosteres
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78
Q

optimisation of lead compound: improve binding in a hydrophobic pocket

A

increasing bulk or chain length
varying ring structure/ring positions

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79
Q

how does an ester eliminate any H bonding (SAR hydroxyl)

A

electronically: lone pair delocalised (weaker acceptor)
sterically: ester group is bulky and block H bond formation

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80
Q

SAR test of hydroxyl groups (hydrogen bonding)

A

test if H bonding is important to activity
R-OH > R-O-Me removes HBD activity
however, still has HBA activity, so form ester
R-OH > R-O-C(=O)-Me which has neither activity

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81
Q

SAR test of amino groups (hydrogen or ionic bonding)

A

test if H bonding and ionic bonding is important to activity
amine > amide stops lone pair taking part in H bonding
also inhibits protonation because lp delocalises > carbonyl, so no ionic bonds

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82
Q

SAR test of aromatic rings (v.d.w)

A

flat ring has v. strong v.d.w because of proximity to binding site
hydrogenate to remove flatness, weakens/decreases v.d.w because the ring cannot bind as close

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83
Q

SAR test of alkenes (v.d.w & hydrophobic interactions)

A

hydrogenate to alkene, cannot bind as close, decreasing number of interactions

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84
Q

SAR test of ketones (H-bonding & dipole-dipole)

A

reduce > alcohol
carbonyl group is flat, proximity increases interactions
alcohol is tetrahedral, distance decreases interactions
also flips dipole

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85
Q

SAR test of amides (H bonding)

A

hydrolysis > split into amine + carb acid (see if amide is necessary for carbonyl activity)
reduction to amine > disrupts H bonding of carbonyl (removed)
(see if carbonyl is necessary)

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86
Q

SAR test: bioisosteres

A

replace with atom of same valency

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87
Q

what does C mean w.r.t QSAR

A

concentration of drug required to reach defined level of biological activity

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88
Q

IC50

A

concentration required to achieve 50% inhibition

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89
Q

ED50

A

mean effective dose required to produce a therapeutic effect in 50% of test sample

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90
Q

main properties of a drug that appear to influence its activity are

A

lipophilicity
electronic effects
size & shape

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91
Q

hydrophobicity

A

how easily a drug can cross the cell membrane

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92
Q

partition coefficient eqn

A

P = [drug] in octanol / [drug] in water

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93
Q

hydrophobic compounds have _ P values

A

high

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94
Q

straight line eqn for relationship between P value and drug activity

A

log (1/C) = k1logP + k2

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95
Q

relationship between log(1/C) and logP is

A

parabolic

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96
Q

typical logP value for CNS active drug

A

1.75

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97
Q

LogD

A

logP at a particular pH

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98
Q

why is logP pH independant?

A

only takes into account [neutral species]

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99
Q

hydrophobic parameter

A

pi symbol
contribution of each substituent to hydrophobicity

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100
Q

P(H) =

A

partition coefficient for the standard compound

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101
Q

P(X) =

A

partition coefficient for the standard compound with the substituent.

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102
Q

solid phase synthesis requires

A

-inert cross-linked insoluble polymeric support
-anchor or linker
-stable bond between linker & substrate
-simple efficient removal of product from linker
-protecting groups

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103
Q

in 2012, how many drugs violated at least 1 of lipinski’s rules and how many failed more than 2?

A

1 = 16%
>2 = 6%

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104
Q

wang resin used for

A

peptide synthesis

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105
Q

mix and split process

A
  1. pool of beads > separate reaction vessels, each for a different reactant attached
  2. each vessel sees a different 2’ reactant
  3. filter/wash beads and mix all into one
  4. split into 3 equal portions, treat each with a different 3’ reactant
  5. this gives 9 products. repeat.
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106
Q

deconvolution

A

isolating and identifying the most active component in a mixture

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107
Q

micromanipulation

A

each bead in a mixture only contains one structural product; separate beads individually and test

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108
Q

recursive deconvolution

A

test compounds at each stage of synthesis.
test if activity is only detected after addition of a specific component

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109
Q

sequential release

A

split a library by bead into smaller components

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110
Q

tagging (QSAR)

A

2 molecules of interest are built up on the same bead
1 is compound of interest, the other acts as a code for each step.

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111
Q

parallel synthesis

A

reaction carried out in a series of wells to generate a library of chemicals

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112
Q

what is parallel synthesis used for?

A

focused lead optimisation studies

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113
Q

dynamic combinatorial synthesis

A

alternative to split and mix
synthesis and screen in vivo
identify active compounds by stopping reaction
convert eqm products into stable compounds that cannot > starting materials

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114
Q

spider approach (QSAR)

A

attach multiple different functional groups to a central scaffold
increases of finding a compound that will interact with target binding site

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115
Q

fragment based lead discovery

A

design lead compound by identifying epitopes (SM) that bind to regions of active site
link several epitopes together to give lead compound

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116
Q

vebers rules (additional to RO5)

A

rotatable bonds < 10
polar surface area < 140 Å
HBA + HBD <12

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117
Q

what kinds of drugs are exceptions to RO5?

A

antifungals, antibiotics, vitamins and cardiac glycosides

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118
Q

parabolic (Hansch) eqn for log (1/C) and P

A

log (1/C) = -k1(logP)^2 + k2logP + k3

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119
Q

hydrophobic paramater eqn

A

pi,x = logPx - logPh

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120
Q

if the hydrophobic parameter is a +ve value

A

the substituent is hydrophobic

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121
Q

if the hydrophobic parameter is a -ve value

A

the substituent is hydrophilic

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122
Q

the electronic effect

A

if X is EWD it will stabilise the anion, eqm > RHS and K increases

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123
Q

advantages of QSAR

A

Quantifying the relationship between structure and activity provides an under-standing of these effects, not available from raw data

Allows informed predictions, particularly regarding the synthesis of new compounds. Can easily interpolate the data, but must not extrapolate beyond the range of the data set.

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124
Q

disadvantages of QSAR

A

-False correlations may arise through too heavy reliance on biological data (error prone)
-Data set may be incomplete
-Some physicochemical properties are already cross-correlated. Should ideally use independent variables in QSAR.

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125
Q

drug repurposing

A

Use old drugs for a new purpose (indication)
Recycle a molecule, a pathway, a biological activity

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126
Q

advantages of drug repurposing

A

-low cost
-skip animal studies > phase 2
-compounds already availible
-large scale production already established

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127
Q

disadvantages of drug repurposing

A

-intellectual property
-target identification can be more challenging
-SAR to improve potency loses repurposing potential
-effective [drug] often higher in vitro than is viable in vivo

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128
Q

non-specific drug

A

no defined molecular target
act outside of cells
different structures can illicit a similiar pharmacological response

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129
Q

examples of non-specific drugs

A

general anaesthetics

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130
Q

specific drugs

A

direct interaction between drug and target
minor changes in structure can have major effects on activity

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131
Q

describe the structure of Valinomycin

A

circular (micelle like)
hydrophobic on outside, isopropyl groups
hydrophilic on inside, carbonyl groups

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132
Q

give the mechanism of valinomycin

A

slots into membrane and creates a pore for leakage
leaky cell = dead cell

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133
Q

describe the structure and give the mechanism of Gramicidin A

A

15 aa peptide
helical, forms dimers long enough to span the membrane to make a pore
pore for K+
leaky cell = dead cell

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134
Q

is the sugar phosphate backbone of DNA +ve or -vely charged?

A

-ve

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135
Q

width of minor DNA groove (Cai 2009)

A

10 A (Cai 2009)

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136
Q

width of major DNA groove (Cai 2009)

A

24 A (Cai 2009)

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137
Q

how do proteins bind the grooves of DNA

A

through H bonds and non-specific binding interactions. (Cai 2009)

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138
Q

2 modes of action of groove binders

A

reversible inhibition of DNA function &
induce permanent DNA damage

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139
Q

how does the curved structure of Distamycin and Netropsin help their function.
why are they curved?

A

they mimic the curve of DNA and so bonding interactions are consistently strong through the complex with DNA
curved bc of the ox. state of the atoms

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140
Q

how are minor groove binders that bind AT sequences advantageous

A

have antimicrobial and antitumor activity
specific to AT islands, so do not cause damage to healthy cells

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141
Q

C =

A

minimum concentration required to cause a specific biological response

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142
Q

bioactivity =

A

A (hydrophobic parameter) + B (electronic parameter) + C (steric parameter) + D (other parameters) + E

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143
Q

Hansch proposed that drug action can be split into 2 stages

A
  1. transport of drug to the site of action
  2. binding of the drug to the target site
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144
Q

P =

A

partition coefficient

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145
Q

D =

A

distribution coeffient

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146
Q

pi =

A

hydrophobic parameter

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147
Q

sigma =

A

electronic parameter (Hansch substitution constant)

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148
Q

why are steric effects important in drug design?

A

drugs that bind to receptors or enzymes must have a specific size or shape

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149
Q

Es =

A

taft steric parameter

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150
Q

MR =

A

(steric) molar refractivity

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151
Q

if logP values are limited to a short range the eqn will be

A

linear

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152
Q

if logP values are across a greater range the eqn will be

A

parabolic

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153
Q

accuracy of Hansch eqn will depend on 3 things:

A
  1. number of analogues used (greater the no., higher probability of obtaining an accurate eqn)
  2. accuracy of biological data used in derivation of eqn
  3. choice of parameter
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154
Q

n =

A

no. of analogues

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155
Q

craig plot shows that there is no relationship between

A

pi and sigma

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156
Q

6 steps to planning a QSAR study

A
  1. decide physiochemical properties to investigate, using data tables and Craig plot
  2. synthesise enough compounds to make results statistically significant
  3. best to avoid ionisable substituents which many confuse results
  4. best avoid groups that are easily metabolised
  5. dont vary too much at once, consider nature and position
  6. apply state-of-art 3D-QSAR and other computer methods
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157
Q

positive sigma =

A

EWD

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158
Q

negative sigma =

A

ED

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159
Q

positive pi =

A

hydrophobic

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160
Q

negative pi =

A

electron donor

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161
Q

what are common structural and chemical features of intercalators that relate to their function/mode of action?

A

all have a flat (usually aromatic) region that slides between base pairs and a charged group

162
Q

4 main classes of DNA alkylating agents

A

nitrogen mustards
ethyleneimines (arizidines)
methanosulfonates
platinum complexes

163
Q

how to improve selectivity of alkylating agents

A

lowering reactivity by substitution of groups that contribute to electrophile character
i.e. replace N-methyl with N-aryl : lone pair of N interacts with ring pi system so is less able to displace Cl- (nitrogen mustards).
only strong nucleophiles like guanine can then react with the drug

164
Q

what % of drugs act on receptors?

A

40%

165
Q

agonist

A

drug which binds to receptor and stimulates same response as endogenous chemical messenger

166
Q

antagonist

A

drug which binds to receptor and stimulates no response, but blocks agonist

167
Q

inverse agonist

A

drug which acts as antagonist, but also eliminates any resting activity associated with a receptor

168
Q

function of receptors

A

-mediate an intracellular response to an extracellular messenger
-the ligand does not react with the receptor

169
Q

where are receptors usually located in a cell?

A

plasma membrane/exterior cell surface

170
Q

specificity of receptor and consequences for drug design

A

very specific proteins wrt shape and binding sites so there must be specific complementary interactions between receptor and drug for activity

171
Q

4 main types of receptor targeted by drugs

A

1) Ion channels
2) G-protein coupled receptors (GPCRs)
3) Kinase-linked receptors
4) Intracellular receptors (aka nuclear hormone receptors)

172
Q

2 main types of ion channels

A

voltage-gated ion channel
ligand-gated ion channel

173
Q

function of ion channels

A

membranes are hydrophobic so ions cannot freely diffuse through membranes
ion channels allow rapid movement of ions across membranes after binding to external stimulus
transmembrane proteins

174
Q

voltage-gated ion channels respond to and are found in what kind of cells

A

electrical stimulus
excitable cells e.g. nerves

175
Q

ligand-gated ion channels respond to and are found in what kind of cells

A

chemical stimulus
ubiquitous, therefore common drug targets

176
Q

what happens when a ligand binds to a ligand-gated ion channel?

A
  • Specific chemical messenger binds to ion channel protein
  • Induced fit of binding causes shape change in protein
  • Ion channel opens, specific ions pass through
  • occurs in milliseconds because the direct consequence of ligand binding is the channel opening
177
Q

synapse

A

point of communication between a neuron and another cell

178
Q

acetylcholine interactions with neurons and ligand-gated ion channels

A
  • common synaptic neurotransmitter
  • Released into synapse from presynaptic neuron
  • Binds to nicotinic acetylcholine receptors (nAChR) on post-synaptic cell membrane
  • Post-synaptic cell becomes permeable to cations, movement of Na+, K+ and Ca2+ which causes post-synaptic response
  • Acetylcholine broken down rapidly; nerves staying “on” is a bad thing
179
Q

how do neuromuscular blockers interact with nicotinic acetylcholine receptors and what is the outcome?

A
  • Nicotinic acetylcholine receptor antagonists are able to compete with ACh for nAChR binding sites
  • Prevent neuromuscular function - i.e. cause muscle paralysis
180
Q

origin and clinical use of nicotinic acetylcholine receptor antagonists.

A
  • Widely used with general anaesthesia in surgery
  • Original source compound: tubocurarine - S. American arrow-tip poison
  • Modern analogues: pancuronium amongst others
181
Q

receptor activated by adrenaline and noradrenaline

A

adrenergic receptor/adrenoreceptor

182
Q

are all receptors that are activated by the same neurotransmitter the same across the body? what does this mean for drug design

A

no, they may have distinct amino acid sequences etc.
can target drug to a specific sub-type of receptor based on its features that are distinct from the other sub-types
i.e. nicotinic vs muscarinic cholinergic receptor

183
Q

describe the induced fit model of receptor-signal binding

A
  • binding site contains specific binding regions which contain functional groups that are complimentary to the binding groups of the messenger
  • messenger fits into the binding site and binding groups interact weakly but fit is not perfect.
  • receptor protein alters shape to bring the groups to obtain a stronger interaction.
  • bonding forces must be large enough to change the shape of the binding site, but not so strong that the messenger is unable to leave.
184
Q

the ion selectivity of an ion channel is based on

A

the amino acids lining the ion channel

185
Q

structure of an ion channel lock-gate and how it is opened?

A
  • lock gate is made up of five kinked α-helices (the 2-TM region) where one helix is contributed by each of the five protein subunits
  • closed state = kinks are pointing towards each other
  • conformational change induced by ligand binding causes each of these helices to rotate such that the kink points the other way, opening up the pore
186
Q

where are voltage-gated ion channels located in the neuron?

A

axon
(Intro to Med Chem P. L. Graham, 2017)

187
Q

function of voltage-gated ion channels

A

react to neuron depolarization/polarisation to produce an action potential -> signal
(Intro to Med Chem P. L. Graham, 2017)

188
Q

describe the mechanism of ligand-gated sodium channels and potassium channels in neurons

A

resting state :
potassium ion channels = open
sodium ion channels = closed

excited :
sodium ion channels = open

189
Q

what are g-protein coupled receptors?

A

are transmembrane proteins which activate an intracellular signalling protein called a G-protein (in response to stimulus).
slower than ion channels, mechanism takes minutes.

190
Q

function of GPCRs

A
  • Mediate response to hormones and slow-acting neurotransmitters
  • e.g. glutamic acid, GABA, noradrenaline, dopamine, acetylcholine, serotonin, prostaglandins, adenosine, opiates, angiotensin, bradykinin, thrombin
191
Q

function of a G-protein

A

initiate a signalling cascade, involving a variety of enzymes

192
Q

structure of GPCRs

A
  • protein chain winds 7 seven through membrane
  • each transmembrane section is helical and hydrophobic
  • G protein binding site on intracellular side receptor, signal binding site on extracellular side
  • each signal molecule has a distinct binding site location
193
Q

GCPR mechanism

A
  1. Specific chemical messenger binds to GPCR, induces conformational change
  2. Conformational change of intramembrane domain affects gamma subunit, results in a swap of GDP for GTP
  3. Dissociation of subunits Ga // BY to distinct membrane-embedded effector molecules elicits signaling cascades
  4. Signaling cascade activates a 2nd messenger molecule which activates a target enzyme.
194
Q

2 main signal transduction pathways regulated by GPCRs

A

cyclic adenosine monophosphate (cAMP) signal pathway
phosphatidylinositol signal pathway

195
Q

how does GPCR initiate cAMP pathway

A
  • Gα-subunit binds to membrane-bound enzyme adenylate cyclase
  • AMP becomes activated, and catalyses synthesis of cAMP from ATP. Chops off 2 phosphate groups and forms ring between O and OH
  • cAMP moves into cytoplasm and activates protein kinase A (PKA)
  • PKA phosphorylates and activates further enzymes with specific function for the cell in question
196
Q

2 main groups of GPCR adrenergic receptors

A
  • α (smooth muscle contraction, inhibition of insulin release)
  • β (increase cardiac output, act via cAMP)
197
Q

example of β-blocker and clinical uses

A

propranolol
- antagonist
- Opposes the action of adrenaline on β-receptors, so used to treat high blood pressure, angina and various dysrhythmias, and used in recovery post- myocardinal infarction

198
Q

3 types of GPCRs

A

adrenergic
muscarinic
opioid

199
Q

3 sub-families of GPCRs

A
  • class A rhodopsin-like receptors
  • class B secretin-like receptors
  • class C metabotropic glutamate-like and pheromone receptors
    (Intro to Med Chem P. L. Graham, 2017)
200
Q

why is the existence of receptor subtypes important?

A

This is important, because one receptor subtype may be prevalent in one part of the body (e.g. the gut) while a different receptor subtype is prevalent in another part (e.g. the heart)
(Intro to Med Chem P. L. Graham, 2017)

201
Q

why is the convergent evolution of GPCRs important? including example

A

greater similarities between receptors which bind different ligands and have evolved from the same branch of the tree
»
similarities between subtypes of receptors which bind the same ligand.
e.g histamine H1 receptor resembles muscarinic receptor > histamine H2 receptor.
- important consequences in drug design : increased possibility that a drug aimed at a muscarinic receptor may also interact with a histamine H1 receptor and lead to unwanted side effects.
(Intro to Med Chem P. L. Graham, 2017)

202
Q

how is the active conformation of kinase receptor different from inactive conformation?

A

active = intracellular domain is phosphorylated

203
Q

what is the effect of kinase receptor dimerisation and why is this important?

A

Dimerisation means primary messenger (signal) must be dimerized too.
Dimerization is important as the enzyme on one side of the dimer phosphorylates the tyrosine of the other enzyme (and vice-versa).
(Intro to Med Chem P. L. Graham, 2017)

204
Q

mechanism of kinase-linked receptors

A
  • minutes to respond
  • Activated by polypeptide hormones, growth factors and cytokines i.e. important in endocrine regulation
  • messenger binds causing shape in protein conformation
  • dimerisation allows each active protein to phosphorylate the other
  • intracellular proteins can now bind to phosphorylated kinase domain
205
Q

kinase-linked receptor structure

A
  • receptor N terminus (transmembrane) and enzyme C terminus (intracellular)
  • Active conformation functions as intracellular kinase enzyme (i.e. signal transduction by phosphorylation)
  • ATP cofactor
  • often tyrosine-linked
206
Q

example of a kinase-linked receptor that is an important anti-cancer drug target

A

Epidermal growth factor receptors (EGFRs)
Inhibition of kinases is possible by blocking the ATP binding site (as kinases use ATP for phosphorylation)

207
Q

how do EGFRs work in cancer?

A
  • EGFRs are a type of tyrosine kinase-linked receptor that are over-expressed and/or abnormal in many cancer types
  • Consist of extracellular EGF binding site and intracellular tyrosine kinase
  • Over-expression of EGFR leads to uncontrolled proliferation of cells
208
Q

how would you target EGFRs with anti-cancer drugs

A
  • Inhibition of kinases is possible by blocking the ATP binding site (as kinases use ATP for phosphorylation)
  • However, targeting an ATP binding site, ubiquitous across all cells, you create many side effects.
209
Q

example of anti-cancer drug targeting EGFRs

A

gefitinib is a competitive inhibitor of ATP binding site
antagonist- lack of phosphate groups

210
Q

difference between type 1 and type 2 inhibitors of kinase-linked receptors

A
  • Type I inhibitors bind to the active conformation of the enzyme, whereas type II inhibitors bind to the inactive conformation.
  • exceptions: Sunitinib and dasatinib are able to bind to both active and inactive forms of the same kinase enzyme and could be defined as type I or type II.
    (Intro to Med Chem P. L. Graham, 2017)
211
Q

SAR of lapatinib type 2 inhibitor of EGFRs

A
  • binds to inactive conformation, allows fluorobenzyloxy substituent to interact with hydrophobic pocket that isn’t exposed in active form
  • chain containing the amine and the sulphonyl group increases aqueous solubility, located in region of active site that’s exposed to solvent
  • potent activity for another receptor tyrosine kinase ErbB-2 (HER2), structurally related to EGFR. ergo, dual-action inhibitor used for cancers that overexpress both EGFR and ErbB-2.
    (Intro to Med Chem P. L. Graham, 2017)
212
Q

mechanism of kinase-linked receptor

A
  • active site closed in resting conformation
  • binding of signal to extracellular region cause conformational change and active site opens
  • tyrosine residues on protein substrate are phosphorylated OR enzyme dimerizes and each monomer phosphorylates the other; and protein substrates dock on phospho-tyrosine
  • ATP cofactor
  • several phosphorylation’s occur so signal is amplified
    (Intro to Med Chem P. L. Graham, 2017)
213
Q

mechanism of intracellular receptors

A
  • Binding of chemical messenger causes shape change
  • active conformation binds DNA and modulates transcription for particular protein
    = transcription factor
  • Slower response than other receptors as rely upon transcription (hours-days)
  • responds to steroid hormones, thyroid hormones and retinoids
214
Q

mechanism of intracellular estrogen receptor

A
  • binds estrogen
  • conformational change opens up AF-2 region and dimerization occurs to allow coactivator to bind, allowing DNA complex to form and (increased) transcription.
    commonly overexpressed in breast cancer
  • DNA binding region: zinc finger domain recognizes particular DNA sequence
215
Q

tamifoxen as anti-cancer drug targeting estrogen receptors

A

Tamoxifen has similar hydrophobicity and size to estradiol but has a protonated (at physiological pH) N so forms an H bond with the receptor.
Prevents transcription from estradiol-responsive genes.
takes 5-10 years to eradicate cancer.

216
Q

raloxifene important functional groups

A
  • synthetic agent binds to the binding site without activating the receptor, prevents estradiol from binding
  • 2 phenol groups which mimic the phenol and alcohol group of estrogen
  • skeleton also hydrophobic and matches hydrophobic character of estrogens tetracyclic skeleton
  • side chain = antagonism; contains an amino group which is protonated and forms a hydrogen bond to Asp-351—an interaction that does not take place with estrogen
  • side chain protrudes from the binding pocket and prevents the receptor helix H12 folding over as a lid so AF-2 binding region is not exposed, coactivator can’t bind and transcription factor can’t form
  • side chain must contain amine group of the correct basicity such that it ionizes and forms the interaction with Asp-351
    (Intro to Med Chem P. L. Graham, 2017)
217
Q

raloxifene as anti-cancer drug targeting estrogen receptors

A

antagonist of the estrogen receptor and is used for the treatment of hormone-dependent breast cancer
- side chain = antagonism; contains an amino group which is protonated and forms a hydrogen bond to Asp-351—an interaction that does not take place with estrogen
(Intro to Med Chem P. L. Graham, 2017

218
Q

HIV structure

A
  • single strand RNA
  • two copies of genome
  • enzymes: proteases, reverse transcriptase, integrase
  • cell membrane and protein capsid
219
Q

HIV life cycle

A
  • infects T cells
    1. Infection: HIV surface proteins gp120 and gp41 and T-cell surface proteins CD4, CCR5 and CXCR4 are crucial
    2. Integration into T-cell DNA: HIV capsid disintegrates (viral protease); viral RNA converted into proviral DNA by viral reverse transcriptase; proviral DNA incorporated into host DNA by viral integrase
    3. Processing of viral DNA: Transcription produces more viral RNA, some is incorporated into new virions, some translated into viral proteins
    4. Release of new viruses: New gp120 and gp 41 incorporate into cell membrane, other viral proteins and RNA congregate on inner membrane surface; budding occurs to release new viruses
220
Q

obvious drug targets for anti-HIV drugs and why

A

viral proteins/enzymes because they are completely distinct from eukaryotic proteins/enzymes.

221
Q

HAART

A

highly active antiretroviral therapy uses combinations of Nucleoside reverse transcriptase inhibitors (NRTIs), Non-nucleoside reverse transcriptase inhibitors (NNRTIs), Protease inhibitors (PIs), Integrase inhibitors

222
Q

structure and function of NRTIs

A

nucleoside pro-drugs
compete with cellular nucleotides for reverse transcriptase
generally effective but relatively toxic

223
Q

mechanism of NRTIs

A
  • competitive inhibition of reverse transcriptase
  • halt DNA synthesis when incorporated into growing DNA chain as they are missing 3’-OH
  • ergo no site for further chain extension so DNA synthesis halts
224
Q

type of inhibition of NNRTIs

A
  • Bind allosteric site adjacent to active site
  • non-competitive, reversible
225
Q

mechanism of NNRTIS

A
  • Binding of NNRTI causes conformational change which inactivates active site
  • No accessible active site = no viral DNA synthesis
226
Q

disadvantages of NNRTIs

A
  • rapid drug resistance
  • Mutations in NNRTI binding site stop drugs interacting with RT
  • Most common mutations: replacement of Lys-103 with Asn (mutant = K103N)
    and replacement of Tyr-181 with Cys (mutant = Y181C)
    -resistance reduced when initially used with NRTIs
227
Q

describe the conformational changes that occur to RT hand structure during catalysis

A

palm contains polymerase active site and non-nucleoside-binding pocket, separated by ~10 Å. T
(i) thumb lifts up to bind nucleic acid
(ii) fingers fold down to capture dNTP substrates in the presence of nucleic acid
(iii) non-nucleoside binding leads to thumb hyperextension.
[Das et al., 2012]

228
Q

advantages of NNRTIs

A
  • Higher selectivity for reverse transcriptase over DNA polymerases than NRTIs hence less toxic / fewer side effects
229
Q

Nevirapine NNRTI structure/interactions

A
  • hydrophobic, as allosteric site has hydrophobic residues
  • one half - interaction with tyrosine residues (aromatic)
  • other half - interaction with leucine and valine residues (aliphatic)
  • additional electrostatic interactions with Lys-103
230
Q

Azidomythine and Lamivudine NRTIs activation mechanism and affinity

A
  • Prodrugs phosphorylated intracellularly
  • negative phosphate groups would inhibit diffusion across hydrophobic cell membrane.
  • Drug also has quite high affinity for host DNA polymerases so induces toxic side effects on host cells.
231
Q

how is Efavirenz suited to reduce resistance to NNRTIs

A
  • Small: can shift binding position when mutation occurs
  • Reduced emphasis on Tyr-181 binding; active vs Y181C
  • Able to interact with main peptide chain of binding site
    via hydrogen bonding
  • Still suffers from lower activity vs K103N
232
Q

how is Capravirine suited to reduce resistance to NNRTIs

A
  • Active vs K103N and Y181C variants
  • Forms 3 H-bonds to main peptide chain in
    active site (in addition to aromatic interactions)
  • Conformationally flexible; can bend itself to fit
    even in mutated binding sites
  • Failed in phase II trials
233
Q

how is Etravirine suited to reduce resistance to NNRTIs

A
  • As above: conformational flexibility means
    drug can adapt to mutants
  • Lots of different interactions, so loss of one
    interaction through a mutation is less
    critical to overall binding
  • Used where NNRTI resistance to other
    drugs has developed
234
Q

What are HIV protease inhibitors?

A
  • example of structure-based drug design
  • Structures designed to mimic reaction transition-state:
    TS is usually more tightly bound to enzyme than substrate or product, so a TS mimic should also display strong binding
235
Q

mechanism of HIV protease

A
  • 2 Aspartic acid residues, one from each subunit. one is protonated and the other deprotonated
  • Amide hydrolysis proceeds via tetrahedral intermediate by asp.acid
  • Selectively cleaves peptides between proline and aromatic residues (Phe or Tyr)
236
Q

Structure of HIV protease

A
  • Dimer; active site at interface of subunits
  • Aspartyl protease: active site contains aspartic acid residue crucial to catalytic mechanism
237
Q

what makes HIV proteases good drug targets

A
  • Peptide cleavage next to Pro is rare; doesn’t occur in mammalian proteases = selectivity
  • Symmetrical; mammalian proteases aren’t
238
Q

how is hydroxyethylamine a good inhibitor of viral proteases

A
  • Inhibitor design requires transition-state isostere:
  • OH mimics OH in TS and binds to Asp in active site
  • Chiral centre; R-configuration preferred
239
Q

tipranavir use and resistance profile

A
  • Non-peptide protease inhibitor
  • Resistance is slow to arise; used in patients with resistance to other treatments
240
Q

saquinavir disadvantages

A
  • Quite low oral bioavailability and 98% bound to plasma proteins
  • High dose required to maintain therapeutically high plasma levels
  • Taken with ritonavir: reduces saquinavir metabolism so higher plasma conc.
  • Simpler PIs developed; lower molecular weight, less peptide character (see text book)
241
Q

saquinavir optimisation from pentapeptide

A
  • Simplify to Phe-Pro dipeptide with hydroxyethylamine link (also weak inhibitor)
  • Add Asn: greater activity than pentapeptide (S2-S2’= key section)
  • Vary Z-group: important S3 interaction with large hydrophobic pocket so large quinoline added
  • Tweak Pro structure (go bigger) and tBu ester (swap for amide: more stable) = final structure
242
Q

HIV protease-substrate interactions

A
  • Substrate is viral polypeptide; cleavage occurs between Pro and Phe / Tyr
  • 8 binding subsites per enzyme; 4 per subunit (only 6 shown)
  • Numbered S1-S4 on one monomer, S1’-S4’ on the other
  • Each enzyme subsite, accepts an amino acid residue of the substrate
  • N and O of each peptide bond in substrate involved in H-bond with enzyme
243
Q

why are peptides bad drugs?

A
  • Poor pharmacokinetics (i.e. poor absorption, metabolic susceptibility, rapid excretion, limited access to CNS, high plasma protein binding)
  • Particular impact on administration: poor oral bioavailability
244
Q

what an HIV protease inhibitor should be, an exception

A
  • Short peptide mimic of viral substrate
  • Linked via transition-state isostere (instead of peptide bond)
  • Tipranavir
245
Q

mechanism of HIV DNA integrase

A
  • Integrase picks up viral DNA (synthesised by reverse transcriptase) and other cellular cofactors to form preintegration complex (PIC)
  • Integrase exposes reactive OH groups on viral DNA 3’-terminus
  • PIC enters nucleus, binds to host cell DNA; integrase reacts with host DNA to expose 5’-phosphate groups
  • Viral DNA couples with host DNA (3’-OH reacts with 5’-phosphate)
246
Q

Function of HIV integrase inhibitors

A

Target the splicing of viral DNA into host DNA by HIV integrase
i.e. swapped for 5 base pairs of host DNA

247
Q

overview of SARS-CoV-2 3 step life cycle

A

attachment and entry
replication and synthesis
viral assembly and release

248
Q

SARS-CoV-2 mechanism of attachment and entry

A
  1. Viral spike protein mediates binding and attachment to peptidase domain of host ACE-2 enzyme.
  2. Once virus is bound, a 2nd host cell surface protein, TMPRSS2, cuts off N-terminus of spike protein, allowing fusion and entry of virus into host cell.
249
Q

spike protein features

A

Sugar chains mask virus from immune system.
membrane bound glycosylated trimer that mediates attachment and entry into host cell
2 subunits

250
Q

important spike protein mutations

A

Alpha = type of H bond interaction changes and addition of aromatic ring when asp-501-tyr.

Delta and Gamma = asp-501-tyr; and glu-484-lys which swaps –ve to +ve charge.

Delta = leu-452-arg, swapping a hydrophobic amino acid to a hydrogen bond forming amino acid. Allows escape from antibodies and increased infectivity as receptor affinity is increased.

251
Q

SARS-CoV-2 mechanism of replication and synthesis

A
  1. Uncoating releases viral genome.
  2. RNA immediately translated into protein by ribosomes in cytoplasm.
252
Q

importance of double membrane vesicles in HIV life cycle

A

create protective micro environment for the viral replication and transcription complex.

253
Q

SARS-CoV-2 mechanism of viral assembly and release

A

Post-translational modification occurs here.
1. Viral genome delivered and bound to nucleocapsid protein.
2. Membrane-bound proteins are packaged around capsid.
3. Vesicles encapsulating new virions combine with host cell plasma membrane and released by exocytosis.
4. Host cell is killed by virus hijacking resources, dampening vital host processes or final exocytosis.

254
Q

mRNA vaccines disadvantages

A
  • Unintended effects
  • Delivery (free mRNA in the body is quickly degraded)
  • Storage (requires lower temperatures than other vaccines)
255
Q

mRNA vaccines advantages

A
  • Safety (no infectious agents produced)
  • Efficacy (generate reliable immune response with few side effects)
  • Faster and ‘cheaper’ to produce
256
Q

how is the SARS-CoV-2 vaccine made in vitro

A
  1. In vitro transcription from a DNA template, with promoter (often T7)
  2. Utilises RNA polymerase (often T7), rNTPs, buffer
  3. 5’ cap added by enzymes
257
Q

Two methods of overcoming immune response to mRNA vaccine

A

Purification (removal of dsRNA)
Introduction of modified bases

258
Q

why is the SARS-CoV-2 mRNA vaccine made in vitro

A

Exogenous mRNA is inherently immunostimulatory, as it is recognized by a variety of cell surface, endosomal and cytosolic innate immune receptors

259
Q

contents of SARS-CoV-2 mRNA vaccine

A

5’ cap
3’ poly-adenosine (Poly-A) Tail
5’ untranslated region (UTR)
3’ untranslated region (UTR)
Coding Sequence (CDS) (for SARS-CoV-2 spike protein)

260
Q

5 common targets of antibacterial drugs

A
  1. inhibition of cell metabolism
  2. inhibition of bacterial cell wall synthesis
  3. interaction with plasma membrane
  4. disruption of protein synthesis
  5. inhibition of nucleic acid transcription and replication
261
Q

how are drugs which target prokaryotic cell metabolism specific?

A

target bacterial metabolic pathways that are not present in animal cells

262
Q

function of drugs which inhibit prokaryotic cell metabolism

A
  • Inhibit bacterial metabolism, but not metabolism of host
263
Q

example of a sulfonamide

A

prontosil
- pro-drug of active sulfanilamide
- azo group readily metabolised
- Effective against Gram-positive bacteria (e.g. pneumococci and meningococci) but not against enterobacteria/Gram-negative (e.g. Salmonella)

264
Q

sulfonamide mechanism

A
  • competitive inhibitors of dihydropteroate synthase
  • enzyme converts PABA -> tetrahydrofolate
  • block tetrahydrofolate biosynthesis, stop DNA synthesis hence stop bacterial cell growth and replication
  • Amine group N lone pair nucleophilic-ly attack (SN2) slightly +ve carbon adjacent to the phosphate group of target molecule.
  • Sulphanilamide binds to enzyme active site and blocks PABA preventing the product synthesis.
265
Q

advantages of sulfonamides

A
  • Human cells unaffected: tetrahydrofolate still vital, but acquired through diet from folic acid
  • long lasting, 1 dose /week
266
Q

what makes bacterial cell walls a good drug target

A

eukaryotic cells don’t have cell walls
undergo lysis when cell wall doesn’t form properly due to osmotic pressures

267
Q

disadvantages of bacterial cell wall synthesis inhibitors

A

only act on bacteria that are stil synthesising cell wall
no activity on fully formed cell walls so immune system is also required to eradicate infection

268
Q

how is penicillin made and its drug target

A

cell wall synthesis (usually Gram +ve)

biosynthesis of penicillin core from valine and cysteine
further analogues synthesised from 6-aminopenicillanic acid
through acetylation of 1’ amine you can make many analogues

269
Q

penicillin mechanism

A
  • inhibits transpeptidase which catalyses final cross-linking step in peptidoglycan synthesis
  • D-alanine–D-alanine -> D-alanine–glycine
  • penicillin mimics D-ala–D-ala and reacts with serine in active site
  • irreversibly blocks active site so enzyme is now useless, incomplete cell wall = leaky cell = dead cell
270
Q

disadvantages of penicillin G and solution

A
  • Acid sensitive (broken down in stomach; administered by injection only)
  • Narrow spectrum of activity (poor activity vs Gram negative bacteria)
  • Highly sensitive to b-lactamases

solution: synthesise analogues, varied in acylamino side-chain

271
Q

penicillin G reasons for acid sensitivity and solutions

A
  • ring strain (4 and 5 carbon rings) is relieved by acid-catalysed β-lactam ring-opening
  • SAR: cannot remove ring strain or C=O, but can add EWD acylamide
    e.g Penicillin V and Ampicillin
  • β-lactam C=O highly reactive to nucleophiles (narrow spectrum of activity, only for Gram +ve)
  • EWD group to remove e- density of C=O, reducing reactivity, add hydrophilic groups which increase activity against Gram -ve
  • greatest effect if alpha to the C=O
  • β-lactamase sensitivity
  • sterically hindered penicillin derivatives won’t fit in active site
  • should also inhibit activity
272
Q

give an example of a β-lactam antibiotic

A

cephalosporins

273
Q

general structure of cephalosporins and advantages/disadvantages of this structure

A

6-membered ring reduces 4-membered ring strain
A
- greater acid stability
- greater β-lactamase resistance

D
- reduced antibacterial activity

274
Q

how are cephalosporin analogues classified and what is the trend in activity?

A

classified by generation, each new generation has a broader spectrum of activity than the last
e.g 1st gen = only active against Gram +ve
4th gen = active against both Gram +ve & -ve with increased potency

275
Q

what are β-lactamase inhibitors and their main advantage?

A
  • weak antibiotics, but irreversible inhibitors of β-lactamase
  • used in combo with penicillin
  • allows reduced penicillin dose and increases activity spectrum
276
Q

examples of β-lactamase inhibitors

A

Clavulanic acid
Sulbactam
Tazobactam

277
Q

mechanism of β-lactamase inhibitor clavulanic acid

A
  • nullifies serine OH group of B-lactamase.
  • Inhibits water molecule approach and instigates a different reaction first.
  • Lysine reacts at slight +ve charge next to O. N attacks to form C=O.
  • Allows drug to do its job without interference from B-lactamase.
278
Q

mechanism of glycopeptide antibiotics

A
  • binds D-ala–D-ala in peptidoglycan
  • caps growing glycan to stop cell wall synthesis
279
Q

function of glycopeptide antibiotics and example

A
  • inhibitors of bacterial cell wall synthesis
  • specific, fixed conformation
  • last resort for Gram +ve
    e.g. vancomycin
280
Q

how does vancomycin prevent cell wall synthesis

A

so large it surrounds/caps D-ala–D-ala to prevent access to glycine

281
Q

what is the main issue with antibiotics that target the bacterial plasma membrane

A

all cells have a plasma membrane, so selectivity is low

282
Q

what is the main aim of antibiotics that target the bacterial plasma membrane?

A

make the membrane and cell leaky

283
Q

give 2 examples of antibiotics that target the bacterial plasma membrane by forming ion channels

A

valinomycin and gramicidin

284
Q

give an example of antibiotics that target the bacterial plasma membrane by causing leakage of small molecules

A

polymyxin B

285
Q

structure of polymyxin B

A

NP
relatively long hydrophobic chain for insertion into plasma membrane
large polar looped domain

286
Q

function of polymyxin B

A
  • selective (ish) for bacterial membranes so quite toxic
  • causes leakage of small molecules like nucleosides
  • ergo lack of nucleosides for DNA and RNA synthesis
  • mostly used for drug resistant Gram -ve
287
Q

how do cyclic peptides act on the bacterial plasma membrane and example

A
  • inserts itself into the plasma membrane and aggregates to form hexamer
  • causes general disruption of membrane leading to uncontrolled ion permeability and cell death
    e.g. daptomycin
288
Q

4 modes of action of drugs that impair bacterial protein synthesis

A
  • prevent binding of subunits
  • interfere with binding with tRNA
  • prevent peptide bond formation between amino acids
  • interfere with translocation of ribosome to next codon
289
Q

how do Oxazolidinones inhibit bacterial protein synthesis?

A
  • prevent ribosome formation by binding specific site on 50S subunit, preventing assembly with 30S subunit
  • broad spectrum Gram +ve bacteriostatic
290
Q

common motifs of Oxazolidinones

A
  • aromatic ring with F substituent
  • oxazolidinone ring
    both form VdW and pi stacking interactions with nuclear bases of ribosomal RNA
291
Q

2 examples of Oxazolidinones

A

Linezolid and Tedizolid

292
Q

how do tetracyclines inhibit bacterial protein synthesis

A
  • binds to 30s subunit, preventing tRNA from binding to the mRNA-ribosome complex
  • aromatic ring forms pi stacking interactions
  • many hydrophilic groups form H bond network with sugar phosphate backbone
  • broad spectrum bacteriostatic
293
Q

disadvantages of tetracyclines

A
  • acid sensitive, cannot eat dairy as lactic acid prevents absorption in gut
  • cannot go out in sunlight -> severe sunburn
  • high resistance due to irresponsible use in agriculture
294
Q

advantages of tetracyclines

A
  • long lasting doses
  • works against both Gram +ve and -ve
295
Q

how do chloramphenicols inhibit bacterial protein synthesis and essential functional groups

A
  • Prevents elongation of peptide chain by inhibiting peptide bond formation.
  • Binds to ‘a’ site of larger subunit and acts by inhibiting movement of whole ribosome unit along mRNA.
  • Nitrobenzyl group essential for binding: pi stacking of aromatic ring and cytosine ring of RNA.
  • Hydroxyl group essential for H bonds with sugar phosphate backbone.
  • Dichloroacetamide group is important but can be modified.
296
Q

advantages and disadvantages of chloramphenicol

A

A
- cheap, broad spectrum bacteriostatic
- readily crosses BBB, used for brain abcesses

D
- side effects: rare and unpredictable aplastic anemia

297
Q

activity-essential macrolide functional groups

A
  • OH forms H bond to adenine base in 50S subunit. If this is mutated drug cannot bind.
    • Large macrolide lactone ring forms VdW interactions in the ribosome, in a hydrophobic exit tunnel; ring sits there and blocks it (blocking translocation).
298
Q

how do macrolides inhibit bacterial protein synthesis and spectrum of activity compared to penicillin

A
  • bind 50s subunit to prevent translocation = shift of ribosome along mRNA to expose next codon for translation
  • wider spectrum of activity against Gram +ve than penicillin
299
Q

example of macrolide antibiotic and a related family

A

erythromycin
macrolides are polyketides, a related family is ketolides which are more potent, with a broader spectrum and active against macrolide-resistant strains

300
Q

functional groups of erythromycin that make it acid-sensitive and solution to allow oral administration

A
  • C=O at position 9
  • OH at positions 12 and 6
  • OH lone pairs act as nucleophiles and attack C=O to form ketyl structure which prevents binding to ribosome

solution: coated in strong shell allowing passage through stomach

301
Q

structure of macrolide antibiotic

A
  • large (14,15 or 16-membered) macrolide lactone ring decorated with sugars
    • forms VdW interactions in the ribosome, in a hydrophobic exit tunnel; ring sits there and blocks it (blocking translocation).
  • Hydroxyl and tertiary amine group are essential for activity.
    • Hydroxyl forms H bond to adenine base in 50S subunit. If this is mutated, i.e. adenine is no longer present, the drug cannot bind.
302
Q

how do aminoglycosides inhibit bacterial protein synthesis

A

Block peptide translocation by binding 30S subunit.
inhibit protein synthesis
peptide chains are released before they are finished
many little hydrophobic peptides floating around, insert themselves into cell membranes and cause leaks
knock-on effect classifies aminoglycosides as bactericidal

303
Q

why is mycobacterium TB difficult to kill

A

outer waxy coating not easily penetrated by drugs

304
Q

how are aminoglycosides administered and why

A

intravenously, poorly absorbed by gut and are used for treatment of serious infections.
effective against most aerobic Gram -ve

305
Q

examples of key aminoglycoside antibiotics

A

streptomycin
kanamycin
gentamicin
neomycin

306
Q

how can antibiotics, e.g. kanamycin, be used for molecular cloning

A
  • kill off bacteria that don’t contain desired gene
  • Usual marker are antibacterial resistance genes.
    kanamycin:
  • Hydroxyl group has key interaction.
  • Gene product phosphorylates hydroxyl group to prevent binding to 30S subunit.
  • Phosphate group and sugar phosphate backbone have repelling –ve charges.
  • Stable over many temperatures, can be used with thermophilic bacteria.
  • Works in both Gram +ve and –ve.
307
Q

antibacterial resistance genes of kanamycin

A

neomycin phosphotransferase

308
Q

antibacterial resistance genes of chloramphenicol

A

chloramphenicol acetyltransferase

309
Q

antibacterial resistance gene product against tetracycline

A

tetracycline efflux transporter

310
Q

antibacterial resistance genes of erythromycin

A

methylase

311
Q

antibacterial resistance genes of ampicillin

A

beta lactamase

312
Q

how do antibiotics inhibit bacterial nucleic acid transcription and replication

A

either
- act upon enzymes that manipulate bacterial DNA
- interact directly with bacterial DNA

313
Q

how do aminoacridines inhibit bacterial nucleic acid transcription and replication

A
  • DNA intercalators: large, flat heteroaromatic system
  • distort helix, preventing replication and transcription
  • not selective for bacterial DNA and so too toxic to use for systemic infections
314
Q

how do quinolones and fluoroquinolones inhibit bacterial nucleic acid transcription and replication

A
  • topoisomerase inhibitors
  • bacterial topoisomerases are distinct enough from eukaryotic for selectivity
  • bacteriostatic
315
Q

4 examples of antibacterial quinolones and fluoroquinolones

A

nalidixic acid
enoxacin
ciprofloxacin
grepafloxacin

316
Q

how do rifamycins inhibit bacterial nucleic acid transcription and replication

A
  • Inhibition of bacterial DNA-dependent RNA polymerases prevents the start of bacterial RNA synthesis
  • bind to a site on the bacterial enzyme not present on the respective mammalian enzyme, hence highly selective
  • polyketide NP
317
Q

what is a disadvantage of using rifamycin to treat TB

A
  • TB is slow growing
  • ergo transcription will be slow
  • drugs must act over long timescale but most are heat/acid-sensitive
  • treatment is long process
318
Q

disadvantages of morphine use

A
  • depression of respiratory centre
  • tolerance and dependence (addiction)
  • excitation and euphoria
  • constipation (µ receptors in gut)
  • nausea
  • pupil constriction
319
Q

advantages of morphine use

A
  • analgesic and sedative
  • one of the most effective painkillers
  • elevates pain threshold (decreases brains awareness of pain)
  • great control of constant pain
320
Q

how does morphine act as an analgesic

A
  • acts on CNS cells to disrupt pain signals
  • via opioid receptors e.g. µ, κ and δ
  • these receptors exist as we need control over pain
321
Q

examples of opioid peptides/natural ligands of analgesic receptors

A

endorphins
endomorphins
dynorphins
enkephalins

322
Q

similarities between µ, κ and δ-opioid receptors

A
  • distribution: mostly CNS, µ also found in digestive tract and respiratory system
  • receptor type: all GPCRs, morphine agnist against all 3
  • analgesic activity mediated by various transduction mechanisms which links receptors to neuronal ion channels
323
Q

effect of morphine agonism on µ receptor

A
  • strongest sedative and analgesic effect due to tightest binding
  • respiratory depression
  • euphoria and addiction
  • constipation
324
Q

effect of morphine agonism on κ receptor

A
  • lower levels of analgesia and sedation than µ
  • no respiratory depression
  • no addiction
  • dysphoria and hallucinations
325
Q

effect of morphine agonism on δ receptor

A
  • analgesia without sedation
  • evidence for respiratory depression is mixed (most likely at high doses)
  • no addiction
326
Q

how does morphine imitate natural ligands of opioid receptors

A
  • natural ligands often have terminal tyr
  • morphine imitates tyr OH substituted aromatic ring and tertiary amine
327
Q

important structural features of morphine

A
  • pentacyclic alkaloid with many stereocentres
  • rigid, T shape
  • many important chiral centres
328
Q

how is morphine-derivative, pro-drug codeine orally available

A

one of the hydrophilic OH groups is masked
OH -> OMe
can cross BBB also

329
Q

SAR morphine

A

6-OH
- Masking 6-OH with less polar group increases blood-brain barrier transfer, hence faster accumulation at greater concentration in brain, so greater activity

7-8 double bond
- Removal gives slight increase in analgesia over morphine

necessary groups:
- phenolic OH
- basic nitrogen of N-methyl
- aromatic ring
- stereochemistry

330
Q

3 successful strategies of synthesising morphine analogues

A
  • drug extension
  • drug simplification
  • rigidification
331
Q

mechanism of kinase-linked receptors

A
  • minutes to respond
  • Activated by polypeptide hormones, growth factors and cytokines i.e. important in endocrine regulation
  • messenger binds causing shape in protein conformation
  • dimerisation allows each active protein to phosphorylate the othe
332
Q

mechanism of kinase-linked receptors

A
  • minutes to respond
  • Activated by polypeptide hormones, growth factors and cytokines i.e. important in endocrine regulation
  • messenger binds causing shape in protein conformation
  • dimerisation allows each active protein to phosphorylate the other
333
Q

erythromycin resistant genes and product

A

erm genes:
methylase

334
Q

what is the aim of combinatorial chemistry?

A

find many analogues of a lead compound in one go

335
Q

what is solid phase synthesis and why is it required for combichem?

A

what: starting material linked to solid support
why:
- range of starting materials attached to different beads but treated with same reagent

336
Q

other advantages of solid phase synthesis

A
  • excess reagent/unbound product easily removed so can use large excess of reagent to drive reaction forward
  • intermediates do not need to be purified
  • automation possible
337
Q

5 essential requirements for solid phase synthesis

A
  • Cross-linked insoluble polymeric support inert to the reaction
  • Anchor or linker covalently attached to the support which has a reactive functional group that can used to attach a substrate
  • Bond between the linker and substrate must be stable to the reaction conditions
  • simple, efficient process for removal of product from linker
  • Protecting groups for functional groups not involved in the synthetic route
338
Q

5 common solid synthesis linkers

A
  • merrifield
  • wang
  • rink amide
  • sasrin
  • tetrohydropyranyl
339
Q

reaction conditions for removal of product from each of the 5 common solid synthesis linkers

A
  • merrifield = HF
  • wang = 50% TFA
  • rink amide = 95% TFA
  • sasrin = 1 % TFA
  • tetrohyropyranyl = TFA
340
Q

what is combichem deconvolution

A

the process of isolating and identifying the most active component in a mixture.

341
Q

what is combichem micromanipulation

A

each bead in a mixture only contains one structural product; separate beads individually and test.

342
Q

what is combichem recursive deconvolution

A

test compounds at each stage of synthesis (assuming solid support; alternatively remove some material at each stage for testing).
Test if activity only detected after addition of a specific component

343
Q

what is combichem sequential release

A

Split a library, by bead, into smaller components

344
Q

4 methods to isolate active component from combichem mix and split

A

deconvolution
micromanipulation
recursive deconvolution
sequential release

345
Q

what is combichem tagging

A

two molecules are built up on the same bead. One is the compound of interest; the other acts as a code for each step

346
Q

what aminos make up the Safety-Catch Acid-labile Linker

A

lysine and tryptophan
they each have a free amino group

347
Q

what is the role of lysine and tryptophan in the Safety-Catch Acid-labile Linker?

A

tryptophan = free amino group is the foundation for target structure
lysine = after each stage of synthesis an amino acid is added to the growing peptide

348
Q

how is the Safety-Catch Acid-labile linker removed?

A

cleaved by reducing the 2 sulphoxide groups and then treating with acid

349
Q

what is combichem parallel synthesis

A

technique for focused lead optimisation studies where a reaction is carried out in a series of wells such that a library of single products is generated

350
Q

for what purpose is a lollipop phase separator used

A

when parallel synthesis is conducted in liquid phase to separate the aqueous and organic solutions

351
Q

what is the method of lollipop phase separator

A
  1. pin inserted into mixture of aqueous/organic solution and rapidly cooled to -78 celcius
  2. aqueous phase freezes to pin and be extracted from organic solution
352
Q

how is dynamic combinatorial synthesis different to split and mix

A
  • DCS synthesis and screen in situ
  • Target is in reaction flask with building blocks
  • Reactions should be reversible (amplification of active compound)
353
Q

in dynamic combinatorial synthesis, how do you stop the reaction to identify active compounds?

A

by converting equilibrium products into stable compounds that cannot revert back to starting materials

354
Q

what is the aim/main advantage of dynamic combinatorial synthesis

A

to synthesise a large library of compounds simultaneously in one flask and screen the for activity in situ as they form
much faster

355
Q

discuss the key points of the dynamic combinatorial synthesis of imines from aldehydes and primary amines

A
  • 3 different aldehydes and 4 different 1’ amines = 12 possible imines
  • building blocks mixed with target: carbonic anhydrase
  • after time, sodium cyanoborohydride was added to reduce imines > 2’ amines for identification
  • HPLC shows which products were amplified and therefore which products were able to bind to target.
  • a sulphonamide had significant amplification compared to control with no enzyme present
356
Q

what is the aim of fragment based lead discovery?

A

to find small molecules (epitopes) that bind to specific part of active site.

357
Q

what is the method of fragment based lead discovery?

A
  • screen for small molecules that bind to avctive site of target enzyme
  • epitopes have no biological activity themselves
  • link several epitopes together to give the lead compound which will bind to the whole of the binding site.
358
Q

how many fragment-derived drugs approved for use by FDA and what are their names?
[Wang et al., 2022]

A

4
Vemurafenib
venetoclax
erdafitinib
pexidartinib
[Wang et al., 2022]

359
Q

what are the 2 major challenges of fragment-based lead discovery?

A

Identification of fragment binding to the active site
Subsequently linking/growing the fragments together to form viable ligand

360
Q

rule of 3 for fragment-based lead discovery

A

MW < 300
< 3 HBD
< 3 HBA)
cLogP < 3
< 3 rotable bonds
polar surface area < 60 Å2

361
Q

4 advantages of drug repurposing

A
  • low cost
  • skip animal studies > Phase 2
  • compounds already available
  • formulations and manufacturing chains already established for large-scale production
362
Q

4 disadvantages of drug repurposing

A
  • IP
  • target identification can be more challenging
  • SAR to improve potency loses repurposing potential
  • effective concentrations in vitro too high for in vivo use
363
Q

what is drug repurposing: same target, new virus

A

Antiviral drug which targets a specific viral or cellular function/pathway has activity against other viruses

364
Q

example of drug repurposing: same target, new virus

A

Viral RNA polymerase inhibitors favipiravir (Ebola) and sofosbuvir (Zika)

365
Q

what is drug repurposing: same target, new indication

A

established pharmacological target is found to be essential for another pathogenic process associated with a viral infection (e.g. protein or pathway that can be regulated by an approved drug)

366
Q

example of drug repurposing: same target, new indication

A

Anticancer drug imatinib inhibits cellular Abelson kinase was also found to be active against MERS- and SARS-CoV

367
Q

what is drug repurposing: new target, new indication

A

Approved drug with established bioactivity for a particular target is found to have another new molecular target.

368
Q

example of drug repurposing: new target, new indication

A

antimicrobials that have been found to have a target in virus-infected cells: ivermectin (flaviviruses), azithromycin (Zika)

369
Q

Imatinib effective against SARS-CoV but not SARS-CoV-2

A
  • SARS-CoV relies on ABL2 kinase activity to infect host cells
  • imatinib blocks coronavirus entry via preventing viral fusion with the cell membrane
  • SARS-CoV-2 genome is 80 % homologous with SARS-CoV but imatinib is not effective at clinically appropriate doses
    [Leukemia, 2020, 34:3085]
370
Q

AZT to treat HIV

A

1st anti-HIV drug approved
mode of action: intercalates between bases. NRTI prevents replication.
SAR: flat aromatic region for VdW with bases, +ve charged azo nitrogen for ionic interactions to disrupt -ve backbone.

371
Q

structure of ebola virus genome

A

Linear, single-stranded, negative sense RNA genome (19 kB)

372
Q

chloroquine to treat Zika

A
  • effective in reducing ZIKV vertical transmission in mice
  • CQ suppressed in vitro ZIKV replication in Vero cells with an EC50 of 9.82 mM.
  • CQ interferes in the fusion of envelope proteins with the endosome membrane
373
Q

approved for pregnancy anti-zika drug

A

azithromycin

374
Q

how does SARS-CoV-2 maintain efficient cell entry while evading immune surveillance?

A

The high hACE2 binding affinity of the RBD, furin preactivation of the spike, and hidden RBD in the spike

375
Q

what was the oxford RECOVERY trial?

A

175 NHS hospitals
simple questions asked at enrolment
found 4 effective treatments of SARS-CoV-2

376
Q

what was the WHO solidarity trial?

A
  • > 12,000 patients
  • currently evaluating 3 drugs: artesunate, infliximab and imatinib to reduce mortality
  • initially investigated remdesivir, HCQ, lopinavir and interferon
  • showed these 4 drugs were ineffective against rates of mortality, ventilation and duration of hospital stay
377
Q

Ec50 of remdesivir against ebola vs SARS-CoV-2

A

ebola = 0.003-0.009 uM
SARS-CoV-2 = 0.77 uM

378
Q

RECOVERY oxford trial results with tocilizumab

A
  • improved survival
  • regardless of amount of respiratory support - additional to the benefits of systemic corticosteroids.
  • reduces mortality by 8%.
379
Q

what was the primary clinical use of tocilizumab before SARS-CoV-2

A
  • targets interleukin 6
  • rheumatoid athritis
380
Q

what were the adverse effects of treating patients with HCQ in the oxford RECOVERY trials

A

less likely to be discharged from hospital in 28 days
- higher frequency of invasive ventilation
- higher frequency of death

381
Q

mechanism of action of CQ and HCQ against viruses

A
  • increase pH of endosomes (used by viruses to enter host cell)
  • HCQ interferes with glycosylation of ACE2 (required for SARS-CoV-2 binding)
382
Q

what are lopinavir and why is it used in combination with ritonavir

A

lopinavir is HIV protease inhibitor
ritonavir increases plasma half-life of lopinavir

383
Q

RECOVERY trial results of lopinavir and ritonavir

A

in vitro activity against COVID-19
no benefit found in humans

384
Q

what is the mechanism of azithromycin antibiotic in reducing adverse immune reactions to coronaviruses

A

decreases production if inflammatory cytokines
inhibits neutrophil activation
Used in SARS and MERS

385
Q

RECOVERY trial results with azithromycin

A

no effect on length of hospital stay or mortality with COVID-19

386
Q

clinical uses and possible uses of ivermectin

A

broad spectrum in vivo against
- nematodes, arthropods, flavivirus, mycobacteria
in vitro activity against zika
inhibits dengue virus by blocking an essential viral RNA replication protein 5
contradicting evidence for use against COVID-19

387
Q

anti-viral mechanism of molnupiravir

A
  • targets viral RNA-dependent RNA polymerase
  • incorporates into ssRNA genome of viruses and leads to accumulation of mutations by H bonding with nucleotides
  • amino-M forms 3, imino-M forms 2
  • mutations unrecognizable by viral proofreading
388
Q

results of phase 2 trials of molnupiravir against COVID-19

A

72 structural nucleotide changes to the spike protein compared to 9 in placebo

389
Q

major clinical disadvantage of using molnupiravir

A

targets viral genome so high risk of generating variant of concern

390
Q

what is paxlovid made of and what was it created for

A

Mixture of Ritonavir and protease inhibitor
lead compound for SARS-CoV-2

391
Q

drug target of paxlovid

A

3CL^Pro inhibitor

392
Q

trial results of paxlovid

A

89% effective in patients at risk of serious illness
0/6 people died after admitted taking pax within 5 days of onset cf. placebo 10/41 admitted died

393
Q

what are cell fusion inhibitors and what what are they used for

A

HIV drugs that prevent viral cell membrane from fusing with host cell membrane

394
Q

enfuvirtide drug profile

A

anti-viral cell fusion inhibitor
structure: 36 residue peptide
mechanism: binds to viral protein gp41 involved in pulling host and viral cell together during fusion
- prevents proper gp41 assembly, inhibiting fusion

395
Q

4 disadvantages of anti-viral cell fusion inhibitors

A
  • Expensive: ~$25000 / year
  • Requires injection twice daily
  • Side effects
  • Used as salvage therapy
396
Q

maraviroc drug profile

A

anti-viral cell fusion inhibitor
mechanism: CCR5 antagonist.
- CCR5 is a GPCR co-receptor with host CD4 that mediates host entry
- bind to allosteric site, non-competitive inhibition of gp41-CCR5 binding
- gp41 polymer cannot assemble, inhibiting fusion

397
Q

4 requirements for mRNA vaccine administration system

A
  • Bind vaccine mRNA to form complexes
  • Promote cellular uptake
  • Protect vaccine mRNA from intracellular and extracellular nuclease degradation
  • Enable the release of vaccine mRNA into the cytoplasm
398
Q

5 components of lipid nanoparticles

A
  • ionizable cationic lipid
  • Lipid-linked polyethylene glycol (PEG)
  • Naturally occurring phospholipid (DSPC)
  • Cholesterol
  • Buffers, salt, sugar
399
Q

what are viral vector vaccines

A

a modified version of a different virus (other than the virus you’re vaccinating against)
delivers mRNA vaccine sequence for the antigen to cells
vector itself should not illicit an immune response

400
Q

how are adenoviruses modified to be used as mRNA viral vector vaccines

A

Engineered to remove replication genes (E1)
Propagated in a cell line that complements deletion in trans

BIO3041 medchem (3 decks)

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