Introduction to drug discovery

Question 1

What is a drug?

Answer 1

A substance that has a physiological effect when introduced into the body of a living organism.
A substance intended for use in the medical diagnosis, cure, treatment or prevention of disease

Question 2

What 2 phases can drug discovery be split into?

Answer 2

Drug discovery: finding a compound/agent that has a suitable profile for advancing to clinical trials
Drug development: testing of this agent to (hopefully) demonstrate it is suitable for use in the clinic

Question 3

What steps are in drug discovery?

Answer 3

Target identification
Hit identification
Lead identification
Pre-clinical development

Question 4

What steps are in drug development?

Answer 4

Clinical development Phase 1, 2 and 3
Launch
Post launch (pharmacovigilance)

Question 5

Explain target identification

Answer 5

Projects start with a biological hypothesis - generally a protein.

The role of the protein in disease may come from many sources, including:

• data on target expression in diseased vs normal tissue/patients
• data on association of genetic changes with disease
• off-target pharmacology of known drugs.

Further validate target by looking at the impact of inhibiting or removing the protein in pre-clinical experiments

Question 6

Explain Hit and Lead identification

Answer 6

Once a target has been identified/validated,
the project must then find compounds that
can cause the desired change in the target’s
function.
Sources of new chemical leads include;
i) Natural products
ii) Virtual, fragment or high throughput
screening
iii) Optimisation of known drugs etc

Early chemical ‘hits’ may be developed into
‘lead’ compounds
For some targets other approaches may be
more suitable, e.g. mAbs, gene therapy.

Question 7

Explain Lead Optimisation

Answer 7

In order for a compound to be progressed to
clinical trails it must demonstrate;
The desired biological effect in cell/animal
models (potency)
Suitable human pharmacokinetics (solubility,
permeability, clearance etc).
Likely to be sufficiently well tolerated in
patients. This can be impacted by…
i) Selectivity
ii) Distribution
iii) Formation of reactive metabolites
Also needs to have a suitable development
pathway, including commercial potential
(patent protection)
Finding a compound that achieves all of this is
difficulty, and can be impossible.

Question 8

Explain Pre-clinical development

Answer 8

Once a compound has been identified it is
necessary to do some specific experiments
before human studies can start…
Cross species animal toxicology studies.
These can identify likely toxicological effects in
humans and No Observable Adverse Effect
Limits (NOAELs).
Severe toxicological findings will often stop
the whole project.
Alongside this other groups will work on
developing a drug formulation for trials.
By this point an average project will have
been running for 3-6 years and will have cost
$10-100 million.

Question 9

Explain the steps in drug development

Answer 9

Phase 1: Demonstration of exposure and
initial assessment of safety
Phase 2a: Proof of Principle - Does the drug
alter the target
Phase 2b: Proof of Concept - Does druginduced alteration of the target have impact
on disease progression.
Phase 3: Demonstration of efficacy and safety
in a clinically relevant setting.
Alongside this commercial formulations and
manufacturing processes will be developed.
However, less than 10% of compounds that
enter clinical trails are likely to be approved
for clinical use.
This contributes to an estimated overall cost
of $2.7 billion per new drug approval.

Question 10

What is the DMTA cycle?

Answer 10

Optimisation of a lead:

• Design of compounds
• Synthesis of compounds (Make)
• Testing of compounds
• Analysis of data

Question 11

What is a Hit?

Answer 11

A compound with biological activity in a basic model

Question 12

What is a lead?

Answer 12

A compound with
biological activity in
in vitro models (and
reasonable drug-like
properties)

Question 13

What is a candidate drug?

Answer 13

A compound with
an overall profile
consistent with the
target product
profile

Question 14

How is lipophilicity measured?

Answer 14

The lipophilicity of a compound can be measured by allowing it to partition
between 2 immiscible phases – one aqueous (water based) and one organic
(more fat-like):

D = [C]organic/[C]aqueous

Question 15

What is LogD used to determine?

Answer 15

A logD >0 means more ‘C’ is in organic than aqueous phase: Hydrophobic
A logD <0 means more ‘C’ is in aqueous than organic phase: Hydrophilic

Question 16

What organic solvent is used for almost all logD measurements?

Answer 16

n-octanol

Question 17

What is the importance of ionisation?

Answer 17

This has a significant effect on distribution because the ionised (charged) form cannot
partition significantly into the organic phase.
Water can form interactions with the ionised species well (due to it’s high dielectric
constant/hydrogen bonding capacity), the lipophilic media cannot.

Question 18

What does the composition of the ionised mixture depend on?

Answer 18

pH of the solution

Question 19

Therefore what is logD dependent on?

Answer 19

pH - usually measured at pH 7.4 (physiological pH)

Question 20

How can the partitioning of the neutral form be described?

Answer 20

P = [C]octanol / [Cunionised]water

used to calculate logP

Question 21

What is the partitioning of the neutral form?

Answer 21

constant

Question 22

For neutral compounds, what is the relationship between logD and logP

Answer 22

logD=logP

Question 23

For ionisable compounds, what is the relationship between logD and logP

Answer 23

logD ≤ logP

Question 24

what does D = ?

Answer 24

D = P x %unionised

Question 25

what does % unionised = ?

Answer 25

100/1+10^(charge(pH-pKa))