Andy Watts Lecs

Question 1

What does NDA stand for

Answer 1

New drug application

Question 2

What’s the aim of genomics, proteomics and biopharm

Answer 2

Potentially producing many more targets and “personalised targets”

Question 3

What’s the aim of high throughout screening

Answer 3

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

Question 4

What is virtual screening?

Answer 4

Using a computer to predict activity

Question 5

What’s combinatorial chemistry

Answer 5

Rapidly producing vast numbers of compounds

Question 6

What’s molecular modelling

Answer 6

Computer graphics and models help improve activity

Question 7

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

Answer 7

Tissue and computer models begin to replace animal testing

Question 8

What suitable chemical properties does a drug molecule need

Answer 8

1) chemical stability
2) solubility
3) pKa

Question 9

What 7 suitable biological properties does a drug molecule need

Answer 9

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

Question 10

Define genomics

Answer 10

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

Question 11

What’s the aim of genomics

Answer 11

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

Question 12

What does combinatorial chemistry involve

Answer 12

A scaffold and attaching different functional groups

Question 13

Generic algorithm encodes what

Answer 13

Orientation of compound and rotatable bonds

Question 14

What’s the aim of receptor surface analysis

Answer 14

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

Question 15

What in vitro ADME models based on

Answer 15

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

Question 16

Give an examples of in vitro ADME Model

Answer 16

CACO-2 tissue closely resembles the lining of the stomach

Question 17

What does IND stand for

Answer 17

Investigational new drug application

Question 18

What is meant by attrition

Answer 18

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

Question 19

What does a drug molecule possess

Answer 19

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

Question 20

Gives four properties required for drug like molecules

Answer 20

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

Question 21

Give an example of a product of traditional drug discovery

Answer 21

Conotoxins as ion-channel inhibitors

Question 22

Two types of drug discovery

Answer 22

1) traditional

2) modern

Question 23

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

Answer 23

Anti-histamines as histamine antagonists

Question 24

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

Answer 24

1) ACh
2) histamine
3) gastrin

Question 25

Two histamine receptors

Answer 25

H1- conventional antihistamines | H2- hypothetical

Question 26

Which histamine receptors did they aim to target

Answer 26

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

Question 27

Who began the cimetidine program and when

Answer 27

Smithkline and French in 1964

Question 28

Name the 7 compounds in the rational drug discovery of cimetidine

Answer 28

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

Question 29

Explain 4-methyl histamine

Answer 29

Highly selective agonist

Question 30

Describe Na-guanylhistamine

Answer 30

Weak antagonist and partial agonist

Question 31

Describe burinamide

Answer 31

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

Question 32

Describe thiaburinamide

Answer 32

Enhanced antagonistic activity

Question 33

Describe metiamide

Answer 33

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

Question 34

Is ranitidine better than cimetidine?

Answer 34

SHYEH 10 times more active Fewer side effects Lasts longer

Question 35

What are the two main differences of ranitidine compared to cimetidine

Answer 35

1) nitroketeneaminal group replaces cyanoguanidine | 2) furan ring replaces imidazole ring

Question 36

Name 5 competitors of cimetidine

Answer 36

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

Question 37

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

Answer 37

Lamitidine and loxtidine

Question 38

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

Answer 38

Water and CO2 | Carbonic anhydrase

Question 39

Give an example of a product produced by modern drug design

Answer 39

Influenza anti-virals: neuraminidase inhibitors

Question 40

What is haemagglutinin required for on the influenza virus

Answer 40

Required for attaching the influenza virus to cell surface

Question 41

What's the neuraminidase required for in the influenza virus

Answer 41

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

Question 42

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

Answer 42

Sialic acid

Question 43

In the influenza virus what does M2 function as

Answer 43

Functions in uncoating and virus maturation

Question 44

What do some pathogens have to facilitate infection/propagation

Answer 44

Neuraminidases

Question 45

Name two current competitive neuraminidase inhibitors

Answer 45

Zanamivir (relenza) | Oseltamivir (tamiflu)

Question 46

What's the advantage of the current neuraminidase inhibitors

Answer 46

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

Question 47

What is the relevance of transition state analogues

Answer 47

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)

Question 48

How was zanamivir designed

Answer 48

Designed using 3D x-Ray crystal structure

Question 49

What are biological therapeutics

Answer 49

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

Question 50

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

Answer 50

INSULIN DUH 💁🏼

Question 51

What is fuzeon (enfuviritide)

Answer 51

Treatment of HIV | Fusion inhibitor

Question 52

How does fuzeon work

Answer 52

Blocks entry of HIV into cells (CD4 or T cells) | Rationally designed to mimic components of GP41 and displace them, preventing normal fusion

Question 53

How are human proteins modified post translation ally

Answer 53

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

Question 54

Name two types of glycosylation

Answer 54

O-linked | N-linked

Question 55

What's O-linked glycosylation important for

Answer 55

Protein targeting to specific receptors

Question 56

What's N-linked glycosylation important for

Answer 56

Important role in protein regulation and serum half life

Question 57

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

Answer 57

PK properties of

Question 58

What is filgrastim

Answer 58

Human colony-stimulating factor (G-CSF)

Question 59

What is filgrastim used to treat

Answer 59

Neutropenia and a variety of cancers

Question 60

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

Answer 60

FILGRASTIM

Question 61

Name a biological therapeutic that's 36 amino acids

Answer 61

Fuzeon (enfuviritide)

Question 62

Which of the two biological therapeutics are produced synthetically 1) fuzeon 2) filgrastim

Answer 62

Fuzeon

Question 63

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

Answer 63

Filgrastim

Question 64

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

Answer 64

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

Question 65

What's pegylation?

Answer 65

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

Question 66

What's the key two benefits of pegylation

Answer 66

1) reduce immunogenicity | 2) increase hydrodynamic size prolonging circulatory time

Question 67

Name 6 high throughout methods in drug discovery

Answer 67

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

Question 68

Define bioiostere

Answer 68

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

Question 69

What is data mining

Answer 69

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

Question 70

Bioiosteres need to be compatible with what?

Answer 70

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

Question 71

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

Answer 71

Water + CO2 + carbonic anhydrase

Question 72

Is the HR1 domain of GP41 trimeric?

Answer 72

YEAH

Question 73

What is the zipping process during HIV fusion

Answer 73

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

Question 74

Name two disadvantages of fuzeon

Answer 74

Costs £13000 a year | BD by S.C

Question 75

Name 4 ways to produce biological therapeutics

Answer 75

Synthetically Human cell lines Humanised yeast cells Bacterial cells

Question 76

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

Answer 76

Phosphorylation Sulfation Acylation Glycosylation

Question 77

What's O-linked glycosylation important for

Answer 77

Protein targeting to specific receptors

Question 78

What is N-linked glycosylation important for

Answer 78

Plays a role in protein regulation and serum half life

Question 79

How is pegylation achieved?

Answer 79

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

Question 80

What's a scaffold

Answer 80

Metabolically inert and conformationally restrained structural units