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Revision Flashcards

1
Q

Define chiral carbon

A

A carbon atom that is bonded to 4 different groups

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2
Q

Define enantiomer

A

A pair of optical isomers

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3
Q

Define racemic mixture

A

50:50 mixture of enantiomers

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4
Q

Impact chirality has on how drug behaves

A

Enzymes are chiral. Different enzymes will exhibit different enatioselectivities toward a common racemic micxture. One enantiomer is a preferred substrate.

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5
Q

Which amino acids are positively charged

A

lysine
arginine
histidine

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6
Q

Which amino acids are negatively charged

A

aspartate glutamate

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7
Q

Cation-pi interaction amino acids

A

tryptophan
tyrosine
phenylalanine

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8
Q

Bioisostere

A

exchange of an atom or group of atoms with another, broadly similar atom or group of atoms

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9
Q

Isostere

A

Atoms or groups of atoms which have the same number of valence electrons and which have chemical or physical similarities.

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10
Q

Drugs that enter the CNS should have logP

A

> 2

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11
Q

Substituents that are σ < 0

Substituents that are σ > 0

A

electron donating

electron withdrawing

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12
Q

Which proteins are important in development

A

Transporters
Receptors
Enzymes

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13
Q

Similarities between proteins

A

Protein-based

Interactions with LMW

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14
Q

Differences between proteins

A

Enzymes - LMW chemically transformed
Receptors - LMW binds to receptor to pass message and leaves unchanged
Transporters - LMW compound binds to transporter and moved into cell unchanged

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15
Q

Which amino acid is an imino acid

A

Proline has a secondary amino group

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16
Q

Sulfur-containing AA

A

Cystine

Methionine

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17
Q

Hydrophilic anino acids

A

Serine

Threonine

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18
Q

Amide bond characteristics

A

Some double bond character
Rigidity
Planar
Resonance

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19
Q

Which AA at protein surface

A

Polar amino acids

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20
Q

Which AA interior

A

Non-polar and excludes water

Valine, alanine, isoleucine and leucine

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21
Q

Know how a GPCR works

A

1) Agonist binds to receptor which induces change in receptor association
2) GDP is released and replaced with GTP
3) Alpha and beta gamma subunits dissociate
4) Alpha and beta gamma modulate the activity of intracellular

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22
Q

What do full agonists of B1 also use outside of asparagine and aspartate

A

Two conserved serine

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23
Q

Stoichiometry of NET

A

One Na+ and Cl- per noradrenaline

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24
Q

What type of transporter is NET

A

Secondary active

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25
Q

Describe steps of mutagenesis

A
  1. Design primer that introduce mutation
  2. Amplify mutation-containing DNA using PCR
  3. Remove methylated parental bacterial DNA
  4. Confirm mutation using sequencing
  5. Express protein using transfect cells or oocyte injections and check function
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26
Q

How does his-tag work

A
  1. String of 8 histidine fused to end of protein
  2. Tag forms coordination bond with Ni-NTA matrix within a column
  3. Flush
  4. Imidazole used to released his-tag bound proteins which competes for coordination sites
  5. His-tag removed using thrombin digest
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27
Q

For crystals, a protein must be

A

Pure
Stable
Soluble
Large quantities

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28
Q

What is ITC

A

Measures thermodynamic parameters in solution with a ligand and protein

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29
Q

What binding assay is used

A

Fluorescence based assays using intrinsic e.g. tryptophan or introduced F

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30
Q

What is Gltph

A

Bacterial homologue to EAAT2

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31
Q

What can liposome reconstitution be used for?

A

Radiolabelled uptake and fluorescence assay (SPQ quenched)

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32
Q

What information is gained from crystallogaphy

A

Binding of substrate vs competitive inhibitor (TBOA)

Proposed mechanism of transport

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33
Q

What did x-ray crystallography reveal about sialic acid

A
  1. Sialic acid has an imperfect chair structure
  2. Trigonal planar geometry at carboxylic acid
  3. Carboxylic acid is crucial for interaction with arginine residue
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34
Q

What is the life cycle of the flu

A
  1. Neuraminidase hydrolyses terminal sialic acid residues to allow virus access to the cell membrane
    Haemagglutinin recognises sialic acid residues on cell surface
  2. Virus is endocytosed into endosome.
  3. Collapse causes release of (-)ssRNA and RNA polymerase
  4. (-)viral ssRNA copied via polymerase to (+)RNA exits nucleus and acts as mRNA for translation of viral proteins. Copies of (-)ssRNA are also produced in the nucleus and exported into cytoplasm
  5. Capsid proteins self-assemble to encapsulate (-)viral RNA
  6. Budding takes place for exit
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35
Q

Balance of activity between NA and HA

A

If NA activity is too high, the recognition between HA and sialic acid-terminated cell surface receptors is decreased – virion entry is hindered.
If NA activity is too low, then the level of HA-sialic acid recognition is above the threshold that would allow for easy exit and the ready exit of the virion is compromised

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36
Q

What is the development pathway of neuraminidase inhibitors as antiviral agents

A
  1. Create analogue of sialic acid
  2. Sialic acid has imperfect chair structure
  3. Carboxylic acid crucial to interaction with arginine residue
  4. Transition state has trigonal planar geometry at carboxylic acid
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37
Q

What are important intermolecular interactions between sialic acid or zanamivir and neuraminidase

A

Carboxylic acid groups held by 2 invariant arginines

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38
Q

What is the nature of second generation antivirals

A

Ethyl ester used as prodrug instead of carboxylic acid which is not orally active
Change from 4-guanidino group to 4-amino group
Removal of ring oxygen for easier synthesis
Position of double bond changed which affected activity

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39
Q

Briefly describe the general structure of DNA

A

Polar backbone

Hydrophobic interactions between heterocycles

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40
Q

What structural aspects of DNA make it a useful drug target

A
  • Nucleobases: hydrophobicity, presence of heteroatoms, level of unsaturation, specificity of hydrogen bonding, pi-stacking
  • Anionic phosphate backbone .- readily hydrolysable ester linkages
  • Major minor groove
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41
Q

What features would you include in the design of a DNA intercalating compound

A

-Contain planar or heteroaromatic features that slip between the layers of base pairs. AROMATICS
Drugs held in place by VDW with base pairs above and below
- Charged groups which can interact with phosphate backbone

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42
Q

Name two drugs that target DNA

A

Proflavine

Quinine - intercalator

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43
Q

Name a chain terminator and describe the mechanism of action

A

Aciclovir

Acts as false substrate by mimicking nucleotide triphosphates

Must be able to interact with template: guanine base to pair with cytosine

Added to chain
Chain is unable to extend as 3’ hydroxy group is absent in ribose

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44
Q

How is cell uptake of cisplatin controlled

A

Differential in extracellular and intracellular [Cl-]

High plasma [Cl-] mitigates against aquation

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45
Q

How does cisplatin bind to DNA

A

Aquation forms cationic metabolite to react with negatively charged polynucleotide.

Covalently to DNA via the Pt atom which lies in the major group

Binding to N7 atom of guanine

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46
Q

What is the most prevalent Pt-DNA lesion

A

Intrastrand adducts form mostly

Causes significant distortion

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47
Q

What are high-mobility group proteins

A

Recognise Pt-DNA adducts and structure is further distorted and repair inhibited

48
Q

What is heavy metal poisoning

A

Dimethylmercury

Impairs CNS

49
Q

How does chelation therapy work

A

Chelator competes with target binding sites for metal

50
Q

What are some chelating agents in use

A

Dimercaprol for As, Hg, Pb

EDTA for Ca

51
Q

What are some endogenous chelators

A

Metallothionein

52
Q

What does the ideal chelator have

A 
Ligand groups specific to the metal
Polydentate
Forms stable metal-complexes 
Easily excreted
Non-toxic
53
Q

Name a soft donor
hard donor
soft acid
hard acid

A

Sulfur
Oxygen
Cu +
Fe 3+

54
Q

What is a protein therapeutic vs protein biologic

A

> 5500 Da
Biologics include lipids and nucleic acids
Both are products produced by biologic expression system manipulated using genetic engineering

55
Q

5 key advantages of protein therapeutics over SMD

A
  1. SMD cannot mimic highly specialised functions
  2. Well tolerated and unlikely to generate immune response
  3. Avoids gene therapy
  4. Faster approval
  5. Easier patent protection
56
Q

Classify protein therapeutics into categories and give an example

A
  • Enzymatic/regulatory: Factor VIII
  • Targeting: monoclonal antibodies rituximab
  • Protein vaccines: HPV
  • Protein diagnostics: TB
57
Q

Challenges of delivery of protein therapeutics

A

Purity and potency across batches
Protein solubility and stability
Route of administration
Stability in circulation

58
Q

Choice of production system for recombinant DNA depends on

A

Size
Properties
Modification
Humanisation

59
Q

What are some production systems for recombinant DNA

A 
Bacteria
Yeast
Mammalian cells
Transgenic animals
Transgenic plants
60
Q

Describe an approach to protein modification that has been used to improve half-life

A

PEGylation or attachment of albumin

Use an analogue i.e. GLP-1 analgoue

61
Q

Advantages that recombinant production has over isolation and purification from animal source

A
  • Exact product of human gene
  • High specific activity
  • Decreased chance of immunological rejection
  • Efficient and inexpensive production
  • Scalable
  • Allows modification or gene variant with improved function
62
Q

What system is likely best for production of a small cyclic peptide that is a novel treatment for chronic pain

A

Will E.coli allow for disulfide formation in cyclic peptide?

More likely correctly folded and disulfide formed in yeast

63
Q

How to improve therapeutic efficacy? Example

A

Improve uptake into cells by addition of sugar residues e.g. glucocerebrosidase to change glycosylation profile

64
Q

What are key features of therapeutic proteins that must be monitored for bioequivalence

A
  1. Post-translational modifications
  2. Three-dimensional structures
  3. Protein aggregation
65
Q

What is drug specifcity

A

Only one effect within the biological system e.g. antimicrobial in humans where target protein is lacking

66
Q

What is meant by drug selectivity

A

Preferential activity on one target e.g. selection of one isozyme over another similar enzyme

67
Q

What is different between target identification and target validation

A

Target identification means protein X is identified as altered in disease state. Target validation is confirmation that protein X is central to the disease and modulation will treat the disease

68
Q

What are advantages and disarvantages of natural compounds as leads

A

Adv: Unique structures not discovered and can be patented
Dis: Complex mixture of large macromolecules makes it difficult to identify and determine structure + subsequent chemical synthesis

69
Q

What are four types of in vitro assay

A

Affinity – ligand’s binding to the enzyme or receptors
Activity – degree of enzyme inhibition
Efficacy – partial or full agonist
Functional – anti-inflammatory activity

70
Q

What is the rule of 3 for fragment-based lead discovery

A 
MW < 300
No more than 3 HBD or HBA
cLogP = 3
No more than 3 rotatable bonds
Polar SA = 3 X 20 A
71
Q

What is Lipinski’s Rule of 5

A
  1. No more than 5 HBD
  2. No more than 10 HBA
  3. MW < 500
  4. Calculated log P < 5
  5. Exemptions: active transport
72
Q

What are other important aspects of a lead compound

A

Free of toxic functional groups
Number of chiral centres
Ease of synthesis
Patent potential

73
Q

Which residues to protein kinases phosphorylate in humans

A

(Ser, Thr) and Tyr

74
Q

What is the main difference between Type I and Type II kinase inhibitors

A

Type 1 - bind active phosphorylated conformation of the kinase
Type 2 - recognise inactive unphosphorylated conformation

75
Q

What are some kinase targets in cancer therapy

A

Kinases not controlled by normal regulation
Kinase where inhibition generates synthetic lethal prototype
Kinase expressed on tumour or surrounding tissue

76
Q

Example of kinase inhibitor in cancer

A

EGFR signalling
Excessive kinase activity = uncontrolled cell proliferation
Gefitinib (Type I)

77
Q

Example of kinase inhibitor in inflammation

A

Adalimumab

JAK

78
Q

What is the structural basis of kinase (4)

A

ATP binding in deep cleft between lobes
Adenine forms H-bonds with hinge between lobes
Ribose and P3 bind in hydrophilic channel
Conserved activation loop which can adopt multiple conformations

79
Q

Advantages of polypharmacy

A
  1. Targets several pathways
  2. Less probability for drug resistance
  3. Combination therapy with one drug
80
Q

Give Lipinski’s 5 again

A

xd

81
Q

Disadvantages of Lipinski

A

Can restrict creativity

Exceptions for MW, protein hijacking

82
Q

Define prodrug

A

Compounds which themselves are inactive but are converted to an active drug in the body

83
Q

Identify enzymes involved in prodrug transformations

A

Esterase

N-demethylase

84
Q

Example of prodrugs

A

Oseltamivir
Enalapril
Aspirin

85
Q

Explain use of carboxylic acid protecting groups

A

Carboxylic acid is ionised at physiological pH and will not readily cross the gut wall cell membrane

86
Q

Which drug uses a decarboxylase and Trojan Horse

A

Levodopa

AA analogue which uses non-specific AA proteins

87
Q

What is the difference between combinatorial synthesis and parallel synthesis

A

Combinatorial synthesis - mixtures of different compounds in a single vessel
Parallel synthesis - single product in each vessel

88
Q

Why do we N-protect the amino acid

A

A protecting group knocks out the potential reactivity of the amine group. The single reactive group allows for clean chemistry. Deprotection with piperidine

89
Q

Why are there different types of solid supports available

A

Different support for different linkages and couplings

90
Q

What is enzyme-templated synthesis

A

The enzyme was used as the ‘beaker’ to provide a particular shape.

91
Q

Disadvantages and advantages of combinatorial synthesis

A

Adv: not labour intensive, less reactions, reactions can be driven to completion with knowledge reagents can be washed off
Dis: can get false negatives due to intermolecular interactions with other compounds in mixture, have to separate molecules generated, combinatorial compounds cover narrow area in diversity

92
Q

What does PET and SPECT stand for

A

Positron emission tomography

Single photon emission computed tomography

93
Q

How does PET and SPECT differ from other imaging modalities

A

PET and SPECT show function not just structure

94
Q

How do we use PET to investigate pharmacokinetics

A

Drug needs to be radiolabelled. PET isotopes are useful

95
Q

How do we use PET to investigate pharmacodynamics

A

Well-characterised radiotracer specifically targets potential active site of drug to allow study of drug interaction

96
Q

What are the CNS requirements for radiotracers

A
  • 2 < logP < 3
  • High affinity to specific receptor (K1 < 1 nM)
  • High subtype selectivity
  • High specific activity (> 1000Ci/mmol)
  • High ratio specfic to non-specific binding
  • Metabolic stability during time of measurement
97
Q

Describe fDG metabolism

A

FDG is an analog of glucose
It is transported from blood across the cell membrane by the glucose transporter
It becomes phosphorylated in the cytoplasm by the enzyme hexokinase to form FDG 6-P
Unlike glucose, FDG is not metabolised further and is effectively trapped in the cell

98
Q

Advantageous impact of natural products on drug discovery

A

Plants have evolved to produce unusual compounds to prevent animals and insects from eating them. Drug design would not be able to hit on unusual motifs

99
Q

Several examples of natural products in clinical use

A

Morphine
Paclitaxel
Penicillin

100
Q

Define semisynthesis

A

A precursor that is available in larger yields can be converted chemically/enzymatically to the desired drug

101
Q

Define precursor directed biosynthesis

A

Give bacteria an analogue of its normal substrate

102
Q

Describe mutasynthesis

A

Knockout sequence in bacterium for precursor and use your own substrate

103
Q

Design a separation strategy based on ion-exchange chromatography for a mixture of given compounds

A

Uses: ionic groups (-SO3- or -N(CH3)3+) covalently attached to the stationary solid phase, usually a resin. Solute ions are attracted to the stationary phase by electrostatic force
Depends on anion exchange or cation exchange

104
Q

Negatives of natural compounds on drug design

A
  • Periodic declines in natural products as lead compounds
  • Difficult synthesis of complex structure
  • Often difficult to obtain sufficient concentrations from natural sources
  • Environmentally unsustainable in some cases
105
Q

Which pathway do you get more diversity of natural compounds

A

Secondary metabolism - pathways for modifying metabolites of restricted occurence

106
Q

Why are steric effects important parameters for drug design

A

They affect the SA andvolume

107
Q

Why are electronic effects important parameters for drug design

A

They affect pKa, the charge and electrostatic potential

108
Q

Why are lipophilic effects important parameters for drug design

A

They affect hydrophobicity and log P

109
Q

Why are H-bonding effects important parameters for drug design

A

They affect number of HBD, HBA, logP and conformation

110
Q

What is the DFG motif

A

Three AA at the beginning of the A-loop which type II inhibitors recognise in a DFG-out conformation

111
Q

Each type I or type II kinase inhibitor has at least one H-bond to what region

A

Hinge region

112
Q

How does PEGlyation or fusion with albumin/immunoglobin increase drug efficacy and tolerance

A

Masks protein surface = decreased immune recognition
Decreased proteolysis
Decreased GFR

113
Q

Opium vs morphine

A

Morphine is main active alkanoid in opium

114
Q

Main uses of opioids

A

Analgesia
Anti-diarrhoea
Sedative

115
Q

What is a pharmacophore

A

Atoms and functional groups required for a specific pharmacological activity

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