MP2 Drug discovery

Question 1

what happens in the preclinical phase of drug discovery?

Answer 1

first testing in animals

Question 2

what happens in the clinical development / trials of drug discovery?

Answer 2

the drug is tested in humans

Question 3

state 3 pre-requisites of modern drug discovery

Answer 3

• detailed understanding of the disease
• identification of a specific ‘target’ for the drug
• simple assay to detect drug-target interactions in vitro

Question 4

what must be understood about the disease before drug discovery can begin?

Answer 4

• cellular mechanisms involved
• biochemical pathways involved

Question 5

one of the pre-requisites of modern drug discovery is identification of a specific ‘target’ for the drug. what could this be? what else should be known?

Answer 5

• eg. enzyme, membrane receptor, DNA, RNA
• be aware of the area to which the drug will bind to the target
• know chemical (and 3D) structure
• know cellular and biochemical effects of drug binding to target (eg. will they release something?)

Question 6

a pre-requisite of modern drug discovery is a simple assay to detect drug-target interactions in vitro. what does this assay need to be?

Answer 6

• quick and cheap
• eg. fluorescence, change in colour etc.

Question 7

what are the 4 stages of drug discovery?

Answer 7

• screening a new compound collection
• finding ‘hits’
• finding ‘lead’ compounds
• finding ‘New Drug Candidates’

Question 8

explain the first stage of drug discovery: screening a compound collection

Answer 8

• existing compounds of New Chemical Entities (NCE)
• around 10 000

Question 9

explain the second stage of drug discovery: finding ‘hits’

Answer 9

• compounds that interact with the target (positive response in the assay)
• around 250

Question 10

explain the third stage of drug discovery: finding ‘lead’ compounds

Answer 10

• the best ‘hits’ or ‘hits’ optimised through QSAR (Quantitative Structure Activity Relationships)
• around 10-20

Question 11

explain the fourth stage of drug discovery: finding ‘New Drug Candidates’

Answer 11

• optimised ‘lead’ compounds
• around 3-5

Question 12

where does the compound collection come form for the first stage of drug discovery?

Answer 12

• natural products
• compound libraries
• computational simulations

Question 13

describe the section of the compound collection: natural products

Answer 13

• molecules from plants, animals, microorganisms, fungi …
• they must be isolated form the source
• tend to be bulky and not able to cross intestinal epithelium so must be injected most of the time
• huge potential (only a fraction of living species have been explored)
• in specialised companies (too expensive and risky for Big Pharma)

Question 14

describe the section of the compound collection: compound libraries

Answer 14

• huge collections of compounds synthesised previously for other targets or diseases
• large numbers of new compounds (thousands) synthesised by ‘combinatorial chemistry’
• used by Big Pharma
• machine reorganises the ‘beads’ into different compounds (the more beads there are, the more combinations that can be made - shown in image)

Question 15

describe the section of the compound collection: computational simulations

Answer 15

• modelling of the interactions between ‘virtual’ compounds and the target by powerful computers
• best ‘virtual’ compounds are then synthesised and screened
• the most important approach nowadays (cheaper!)

Question 16

how are the compounds from the compound collection screened for activity in the first stage of drug discovery?

Answer 16

‘High throughput screening’ (HTS)

• thousands of compounds tested at the same time in a single experiment (a few wells of the tray are left empty as negative controls, the rest have pharmacological targets bound to them)
• the reagent is added then colour change or fluorescence occurs (must be repeated to avoid false positives)
• robotic instrumentation (automated)
• rapid results obtained

Question 17

how are the ‘lead’ compounds selected form the hits found in the assay?

Answer 17

must be potent (active at low concentration)
- lower doses will be needed in patients, high doses are unrealistic

must be selective (low interactions with other targets / proteins)
- lower risk of unwanted side effects and adverse effects

must show ‘drug-likeness’!

Question 18

what 2 things is drug-likeness made up of?

Answer 18

• correct physico-chemical properties
• correct ADMET

Question 19

what is meant by the ‘correct physicochemical properties’ in drug-likeness?

Answer 19

• low molecular weight (<500 Da)
• hydro-lipophilicity balance
• solubility in water / buffers
• chemical stability
• other properties (extra tests are performed on hits/leads for solubility, stability etc.)

Question 20

what is meant by the ‘correct ADMET’ in drug-likeness?

Answer 20

• absorption
• distribution
• metabolism
• excretion
• toxicity

Question 21

why is each component of ADMET important to consider in drug discovery?

Answer 21

critical for a drug to have a therapeutic benefit in vivo

A: drug must get into the body across a biological barrier

D: drug must get into the correct organ or tissue

M: drug must not be transformed into another chemical entity to a large extent (unless it’s a pro-drug), if it is completely degraded in the liver it will have no therapeutic effect

E: drug must not be eliminated too quickly

T: drug must be safe

Question 22

how are the ‘drug candidates’ selected?

Answer 22

• must show many critical properties (compromise must be found)
• 5 years is needed for drug discovery to find 3-5 compounds that can progress in the process