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biological chemistry 2 > fundamentals of medicinal chemistry > Flashcards

fundamentals of medicinal chemistry Flashcards

1
Q

where do drugs come from

A

lots have originated from plants/herbs

biologically active so can be used in many settings and be manipulated

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2
Q

folklore and traditional medicines

A

discovered by serendipity or by chance

atropine - muscarinic antagonist

morphine - opiod agonist

quinine - antimalarial

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3
Q

venoms and toxins

A

all poisons so dose is very important

using these has helped to study receptors, ion channels and enzymes

examples - epibatidine, captopril

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4
Q

intentional screening of natural sources

A

taxol - anticancer

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5
Q

the process of drug discovery design and development

A
  1. hit (initial starting point, a compound that has some of the properties you want)
  2. lead (improved version with most of desired properties)
  3. pre-clinical candidate
  4. clinical candidate

these first 4 steps are medicinal chemistry

5 clinical trial in humans

  1. regulatory approval and licensing
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6
Q

design make test cycle

A

design - which compounds to make?
- use computational models, structural biology data, structural activity relationships

make - how are we going to make these?
- use short reliable synthetic routes, late stage diversification, keep costs low

test - how do we know they work?
- biological assays, stabilise, toxicity

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7
Q

structure activity relationships SARs

A

drugs can either be

structurally specific - acting at specific sites, structure is key to function so change in structure affects function

or

structurally non specific - change in structure has little affect on function, act more with physicochemical properties

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8
Q

structurally specific drugs

A

the biological activity of compound depends on precise arrangement and specific features
- structural precision
- targeted interactions
- selectivity

example
- binding to receptors
- enzyme inhibitors

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9
Q

structurally non specific

A

biological activity is influenced by general properties
- broader mechanisms of action
- less dependency of exact structure
- lower target selectivity

examples
- general anaesthetics
- antiseptics

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10
Q

structure and importance

A

when it comes to understanding the drug and its SARs

it can help to be useful to known what can be removed to simplify the structure of improve ligand efficient

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11
Q

determining the important parts of drug

A

when looking at a drug, can identify the different functional groups
- oh = possible hydrogen bonding
- van der Waals groups
- ionic groups

design analogues and test them
- removing a group whilst keeping others and seeing how they interact

some parts my be insignificant
result in either loss or improvement of function

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12
Q

types of interactions a drug can have

A

electrostatic/ionic interactions

hydrogen bonding

dipole/dipole interactions

van der Waals

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13
Q

functional group modifications

A

we do this to improve potency, specificity, duration of action, reduce toxicity, make water soluble

this typically involves
- molecular simplification
- homologation/chain branching - can make new interactions
- ring chain transformation = make a compound more or less rigid
- functional group changes

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14
Q

bioisosteres

A

functional groups with physical and chemical similarities which produce broadly similar biological effects

1- identify key pharmacophoric features
2- improve physiochemical properties
3- remove metabolic liabilities
4- improve synthetic accessibilty
5 - identify novel chemotypes and patent

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15
Q

scaffold-hopping

A

changing core structure but keeping the peripheral groups similar
retains bioactivity but legally a new compound
often called, me-too drugs

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16
Q

examples of bioisosteres

A

-ch3 -nh2-oh-f

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17
Q

pharmacophores

A

maps the 3D presentation of groups required to give the required activity - not necessarily the optimal

often found in many different drugs with same mode of action

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18
Q

importance of knowing pharmacophores

A

can identify other extraneous groups/positions that can be modified to enhance properties without affecting activity

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19
Q

privileged structures

A

common structures found in very different acting drugs
not a pharmacophore - no commonality,
could be easy to synthesis - attractive for starting drug design

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20
Q

enzymes

A
  • provide suitable environment and a reaction surface
    brings substrates together
    positioning the reactants
    weaken bonds
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21
Q

enzyme interactions

A

ka = binding

kd = unbinding
Kcat= reaction

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22
Q

transition stage and drug

A

design drugs that act like the transition stage of enzymes as these can bind the most - greatest affinity and disrupt process the most

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23
Q

protein ligand or drug interactions

A

protein + lig –><– protein ligand complex

depending on the affinity causes the equilibrium position to change position - higher affinity, favouring forward, lies to right, more complex present

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24
Q

kd

A

conc of ligand required to half-saturate the binding site

a low kd means tight binding

25
Q

measuring dissociation constants

A

measure the fraction of total binding sites on the protein, that are occupied by ligand (0)

the range of values (0), range from 0, empty sites, to 1, max occupied

26
Q

proximity effect

A

the specific amide bond of peptide substrate is position at the active site with proper spatial relationship for east to occur

27
Q

high specificity of active sites

A

only correct chemical structure of sub fits in active site

28
Q

acid base catalysis

A

providing protons and/or removing protons

e.g steroid delta isomerase

the active site holds substrate close

29
Q

nucleophilic catalysis

A

provides a lone pair donors and forms new temporary covalent bonds

TEV proteases uses a catalytic triad

30
Q

inhibitor of enzymes

A

inhibitor is a substance that decreases the rate of enzyme catalysed reactions

if an enzyme plays a role in disease - good target for enzyme inhibitor

31
Q

competitive inhibitors

A

compete with substrate for binding to active site , blocking it

V max Is unchanged but Km changes, increasing it

32
Q

uncompetitive inhibitors

A

inhibitor binds with substrate enzyme complex

both Max and Km reduce

33
Q

non competitive inhibitors

A

binds at allosteric site inspire preventing substrate binding

doesnt alter Km, but decreases Max

34
Q

measuring enzyme inhibition

A

enzyme inhibition constant = Ki

can be experimentally determined for an inhibitor by measuring enzyme rate (v) with different inhibitor cones at several different substrate concs

when plotting 1/v against inhibitor conc, each conc of substrate gives intersecting lines and where they intersect = -Ki

35
Q

IC50

A

Inhibitor potency

measures enzyme activity in the prescence of different inhibitor cones at sub cons = Km

IC50 is the concentration of a drug or substance needed to inhibit a biological process or target (like an enzyme) by 50%

36
Q

pros and cons of IC50

A

it is convenient, relatively few experiments needed and high throughput

however, depends on substrate conc used in assay and does not tell you about the mode of inhibition

37
Q

what IC50 mean

A

a low IC50 = greater inhibition as a lower conc of inhibition needed to stop activity 50%

chen-prusoff equation brings IC50 and Ki together

38
Q

Ki meaning

A

A smaller Ki means stronger binding because Ki represents the equilibrium constant for the dissociation of the inhibitor from its target.

Ki = [E][I]/[EI], where:
[E]: Free enzyme (or target)
[I]: Free inhibitor
[EI]: Enzyme-inhibitor complex
A smaller Ki means less dissociation of the inhibitor-target complex, meaning the inhibitor binds tightly and stays bound longer.

39
Q

chloesterol

A

key component in cell membranes and a precursor for steroid hormones

it is biosynthesised in the body

too much can lead to cardiovascular disease

it is poorly water-soluble and is transported in blood as LDL or HDL particles

40
Q

HMG-CoA reductase

A

the rate limiting step in cholesterol biosynthesis is catalysed by this enzyme

41
Q

statins

A

important cholesterol lowering drugs

type 1 statins are very potent but have side effects and are hard to synthesis

type 2 have large hydrophobic groups but easier to synthesis and no chiral centres

42
Q

statins as inhibitors

A

they are competitive inhibitors of HMG-CoA reductase, mimic the enzyme and bind to active site more tightly

the polar head group and hydrophobic groups are important for action

43
Q

transition state analogues/inhibitors

A

drugs that mimic a transition state from the reaction should bind more strongly than substrate or product

44
Q

sulphonamides - sulfa drugs

A

act as competitive enzyme inhibitors of dihydropteroate synthesise and blocks biosynthesis of tetrahydrofolate in bacterial cells

there are bacteriostatic - dont kill bacteria, just prevent cells from growing and multiplying as prevents DNA synthesis

45
Q

why are sulpha drugs not toxic to humans

A

Target: Sulfa drugs inhibit the enzyme dihydropteroate synthase, which bacteria need to produce folic acid (essential for DNA synthesis).
Humans: We don’t synthesize folic acid; we get it from our diet.
This selective targeting means sulfa drugs harm bacteria but leave human cells unaffected.

46
Q

irreversible enzyme inhibitors

A

penicillin forms a covalent bond with enzyme active site- impaired catalysis

47
Q

beta - lactam ring

A

cant synthesis these rings by heating beta amino acids unlike y-lactam and epsilon lactate

ring opening will relieve strain

c=o reactive towards nucleophiles

48
Q

MODE OF ACTION PENCILLINS

A

BETA-LACTAM RING MIMICS D-ALA-D-ALA

reaction is irreversible and enzyme inactivated

no D-amino acids in human body so unaffected

49
Q

how drugs get in

A

drugs are absorbed in gut

distrubted to target tissues

metabolised in liver

extracted

50
Q

oral bioafaliablity

A

fraction of administered drug that finally reaches the site of action, represented as %F

often most of drug is metabolised/eliminated

51
Q

lipinksi rule of 5

A

orally bioavailable drugs obey rule of 5

  1. molecular weight<500
  2. hydrogen bond donors HBD max 5
  3. hydrogen bond acceptors HBA max 10
    4.caculated logP<5, measure of compounds lipophilicity
  4. rotatable bonds<10, more flexible=less absorbed
52
Q

prodrugs

A

inactive compounds that are converted in body to active drug

53
Q

acid hydrolysis of beta-lactam

A

highly reactive ring is prone to acid hydrolysis
opening up the ring to form penicillin acid

rate of acid hydrolysis is influenced by N-acyl side chain

54
Q

tackling resistance of drug

A

making something irreversible

design analogues that aren’t recognised by the thing inhibiting it

discover new pharmacophores

55
Q

electrophiles - alkylating agents

A

cause cross linked DNA strands vis aziridine

56
Q

electrophile - Michael acceptors

A

reacts via conjugate addition

57
Q

redox active compounds

A

quinone is redox active and electrophilic

plans polycyclic aromatic binds between DNA base pairs

58
Q

getting a promising candidate drug to market

A

need to consider
- safety and efficacy - ensure non toxic, effective

legal issues - patents, licensing, approvals

chemical and process development - need optimal synthesising, characteristics need to be understood fully

biological chemistry 2 (5 decks)

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