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Drug Design And Discovery > Andy Watts Lecs > Flashcards

Andy Watts Lecs Flashcards

1
Q

What does NDA stand for

A

New drug application

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2
Q

What’s the aim of genomics, proteomics and biopharm

A

Potentially producing many more targets and “personalised targets”

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3
Q

What’s the aim of high throughout screening

A

Screening up to 100,000 compounds a day for activity against a target protein

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4
Q

What is virtual screening?

A

Using a computer to predict activity

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5
Q

What’s combinatorial chemistry

A

Rapidly producing vast numbers of compounds

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6
Q

What’s molecular modelling

A

Computer graphics and models help improve activity

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7
Q

What’s occurs during in vitro and in silico ADME models

A

Tissue and computer models begin to replace animal testing

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8
Q

What suitable chemical properties does a drug molecule need

A

1) chemical stability
2) solubility
3) pKa

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9
Q

What 7 suitable biological properties does a drug molecule need

A

1) bio distribution
2) metabolism
3) half life
4) solubility
5) potency
6) specificity
7) toxicity

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10
Q

Define genomics

A

The branch of molecular biology concerned with the structure, function, evolution and mapping of genomes

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11
Q

What’s the aim of genomics

A

Hope is that this understanding will provide many more potential protein targets and will allow personalisation of therapies

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12
Q

What does combinatorial chemistry involve

A

A scaffold and attaching different functional groups

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13
Q

Generic algorithm encodes what

A

Orientation of compound and rotatable bonds

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14
Q

What’s the aim of receptor surface analysis

A

Optimise the binding of a drug in its receptor by introducing the appropriate pharmacophores onto the scaffold

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15
Q

What in vitro ADME models based on

A

Based around real tissue samples, which have similar properties to those in the body

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16
Q

Give an examples of in vitro ADME Model

A

CACO-2 tissue closely resembles the lining of the stomach

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17
Q

What does IND stand for

A

Investigational new drug application

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18
Q

What is meant by attrition

A

In silico ADME models help reduce attrition- the failure rate of compounds in the late stage

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19
Q

What does a drug molecule possess

A

One or more functional groups positioned in 3D space on a structural fame work that holds the functional groups in a defined position that enables the molecule to bind specifically to a targeted biological macromolecule, the receptor

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20
Q

Gives four properties required for drug like molecules

A

Low MW
not too lipophilic
Not too hydrophilic
Presence of functional groups

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21
Q

Give an example of a product of traditional drug discovery

A

Conotoxins as ion-channel inhibitors

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22
Q

Two types of drug discovery

A

1) traditional

2) modern

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23
Q

Give an example of a product found from modern rational drug design

A

Anti-histamines as histamine antagonists

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24
Q

Name three secretagogues that cause parietal cells in the stomach to release HCL

A

1) ACh
2) histamine
3) gastrin

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25
Q

Two histamine receptors

A

H1- conventional antihistamines

H2- hypothetical

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26
Q

Which histamine receptors did they aim to target

A

H2- hypothetical receptor was thought to be involved in gastric acid reflux

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27
Q

Who began the cimetidine program and when

A

Smithkline and French in 1964

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28
Q

Name the 7 compounds in the rational drug discovery of cimetidine

A

1) histamine
2) 4-methylhistamine
3) Na-guanylhistamine
4) burinamide
5) thiaburinamide
6) metiamide
7) cimetidine

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29
Q

Explain 4-methyl histamine

A

Highly selective agonist

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30
Q

Describe Na-guanylhistamine

A

Weak antagonist and partial agonist

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31
Q

Describe burinamide

A

Moderate antagonist with no agonist activity, too weakly active for oral administration and too basic

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32
Q

Describe thiaburinamide

A

Enhanced antagonistic activity

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33
Q

Describe metiamide

A

Same structure as thiaburinamide but with Me at position 4 on imidazoles ring, 10 times more active than burinamide but thiourea group toxic

34
Q

Is ranitidine better than cimetidine?

A

SHYEH 10 times more active
Fewer side effects
Lasts longer

35
Q

What are the two main differences of ranitidine compared to cimetidine

A

1) nitroketeneaminal group replaces cyanoguanidine

2) furan ring replaces imidazole ring

36
Q

Name 5 competitors of cimetidine

A

1) ranitidine
2) nizaridine
3) famotidine
4) lamitidine
5) loxtidine

37
Q

Which two competitors of cimetidine were taken off clinical trials cos of causing gastric cancer

A

Lamitidine and loxtidine

38
Q

The protons necessary for HCL production in the parietal cells come from what and is catalysed by what?

A

Water and CO2

Carbonic anhydrase

39
Q

Give an example of a product produced by modern drug design

A

Influenza anti-virals: neuraminidase inhibitors

40
Q

What is haemagglutinin required for on the influenza virus

A

Required for attaching the influenza virus to cell surface

41
Q

What’s the neuraminidase required for in the influenza virus

A

Is required for the efficient release of new virions from infected cells

42
Q

What receptor on the cell does haemagglutinin on the influenza virus bind to

A

Sialic acid

43
Q

In the influenza virus what does M2 function as

A

Functions in uncoating and virus maturation

44
Q

What do some pathogens have to facilitate infection/propagation

A

Neuraminidases

45
Q

Name two current competitive neuraminidase inhibitors

A

Zanamivir (relenza)

Oseltamivir (tamiflu)

46
Q

What’s the advantage of the current neuraminidase inhibitors

A

They’re active against all strains of influenza (ABC) and all serotypes (including H5N1)

47
Q

What is the relevance of transition state analogues

A

They represent species of highest energy- most unstable, enzymes have evolved to bind to these so make drugs that mimic the transition states (introduce double bond)

48
Q

How was zanamivir designed

A

Designed using 3D x-Ray crystal structure

49
Q

What are biological therapeutics

A

An introduction to the treatment of disease using biological medicines from living plant and animal tissues e.g vaccines, gene therapy, recombinant proteins

50
Q

In biological therapeutics give an example of the earliest peptide based therapeutic

A

INSULIN DUH 💁🏼

51
Q

What is fuzeon (enfuviritide)

A

Treatment of HIV

Fusion inhibitor

52
Q

How does fuzeon work

A

Blocks entry of HIV into cells (CD4 or T cells)

Rationally designed to mimic components of GP41 and displace them, preventing normal fusion

53
Q

How are human proteins modified post translation ally

A

1) phosphorylation
2) sulfation
3) acylation
4) glycosylation (addition of carbohydrates)

54
Q

Name two types of glycosylation

A

O-linked

N-linked

55
Q

What’s O-linked glycosylation important for

A

Protein targeting to specific receptors

56
Q

What’s N-linked glycosylation important for

A

Important role in protein regulation and serum half life

57
Q

N-linked carbohydrates play an important role in ____ of biological therapeutics

A

PK properties of

58
Q

What is filgrastim

A

Human colony-stimulating factor (G-CSF)

59
Q

What is filgrastim used to treat

A

Neutropenia and a variety of cancers

60
Q

Name a biological therapeutic that’s 175 amino acids and has a MW of 18,800 daltons

A

FILGRASTIM

61
Q

Name a biological therapeutic that’s 36 amino acids

A

Fuzeon (enfuviritide)

62
Q

Which of the two biological therapeutics are produced synthetically

1) fuzeon
2) filgrastim

A

Fuzeon

63
Q

Which biological therapeutic is produced by recombinant DNA technology using E.coli

A

Filgrastim

64
Q

What’s the main disadvantage of filgrastim being produced using E.coli?

A

Product is nonglycosylated and so differs from G-CSF isolated from a human cell

65
Q

What’s pegylation?

A

Process of attaching the strands of polyethylene glycol (PEG) polymer to molecules like peptides, proteins and antibody fragments

66
Q

What’s the key two benefits of pegylation

A

1) reduce immunogenicity

2) increase hydrodynamic size prolonging circulatory time

67
Q

Name 6 high throughout methods in drug discovery

A 
Genomics, proteomics and biopharm
High thoughput screening 
Combinatorial Chem
Virtual screening 
Molecular modelling 
In vitro/ in silico ADME models
68
Q

Define bioiostere

A

A chemical group which can replace another chemical group without affecting the biological activity of the drug

69
Q

What is data mining

A

Need to learn as much info as poss from data- is an implication of informatics

70
Q

Bioiosteres need to be compatible with what?

A

With a variety of conditions in vivo: solubility, absorption, stability, toxicity

71
Q

Where do the protons come for for HCL production in the parietal cells?

A

Water + CO2 + carbonic anhydrase

72
Q

Is the HR1 domain of GP41 trimeric?

A

YEAH

73
Q

What is the zipping process during HIV fusion

A

When the HR2 domain of GP41 coils into the exposed grooves of the trimeric HR1 domain of GP41

74
Q

Name two disadvantages of fuzeon

A

Costs £13000 a year

BD by S.C

75
Q

Name 4 ways to produce biological therapeutics

A

Synthetically
Human cell lines
Humanised yeast cells
Bacterial cells

76
Q

After translation name 4 ways in which human proteins can be further modified?

A

Phosphorylation
Sulfation
Acylation
Glycosylation

77
Q

What’s O-linked glycosylation important for

A

Protein targeting to specific receptors

78
Q

What is N-linked glycosylation important for

A

Plays a role in protein regulation and serum half life

79
Q

How is pegylation achieved?

A

Incubation of a reactive polyethylene glycol (PEG) with the target macromolecule

80
Q

What’s a scaffold

A

Metabolically inert and conformationally restrained structural units

Drug Design And Discovery (4 decks)

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