The document outlines various approaches to drug discovery and development, highlighting the complexities involved in medicinal chemistry, including synthesis, testing, and approval processes. It details the significance of natural products, combinatorial chemistry, high-throughput screening (HTS), and virtual screening in identifying new therapeutic agents. Additionally, it notes the challenges of drug development such as costs, long timelines, and the low approval rate of compounds in research and development.

1. Drug discovery approaches
By:
Edson Ireeta Munanura

2. Medicinal Chemistry
Medicinal Chemistry is the science that deals with
the discovery or design of new therapeutic agents
and their development into useful medicines.
It involves:
• Synthesis
• Structure-Activity Relationships (SAR)
• Receptor interactions
• Absorption, distribution, metabolism, and
excretion (ADME)

3. Intriguing facts about the drug
discovery/dev’t process
• Its takes 10-15 years to successfully introduce
a new drug on the market
• For every 5,000- 10,000 compounds that
enter the R&D pipeline, ultimately only one
receives approval
• On average, R&D of a successful drug costs
$800m to $2Bn.

4. Drug Discovery is a very wasteful game

5. Expenses &revenue curve for a new drug

6. 6
It’s an expensive business
R&D investment in the USA between 1970 and 2004. Source is the PhRMA annual
survey (www.phrma.org/publications/publications/17.03.2005.1142.cfm).

7. Market withdrawals

8. How novel drugs are discovered
• Serendipity
• Ethnobiological approach
• Combinatorial chemistry (synthesis)
• High Throughput Screening (HTS)
• Virtual screening
 receptor-based
Ligand-based

9. Target Protein
Large libraries
of molecules
High Throughout Screening
Hit
experimental
computational
Virtual Screening
Filtering,
QSAR,
Docking
Small Library of selected hits

10. Genome
Project
Target
Identification
Lead Search Development
Issues : ! Human Diversity ----- Customized Drug
! Possible Targets ----- Too many
Solutions for Lead Compound Search :
1. Existing Sample collection : a. Natural Sources scarce
b. Drug Design lead to
homogeneous & specific sets of
compounds.
2. De Novo Design
Too many unexpected & complicated synthesis
3. Combinatorial Chemistry
Drug Development of 21st Century

11. Drug discovery

Initial characterisation

Pre-clinical trials

Regulatory approval sought to start
trials in humans

Clinical trials Phases I, II, III

Submission of marketing/manufacturing
authorisation application to regulatory authorities

Regulatory authorities review
information and grant (or refuse) licences

Product goes on sale

Post-marketing surveillance
Library of compounds

In vitro screening: human/animal
receptor/enzyme assay; reporter system

Hits/lead

Biochemical, tissue or animal model of
function

lead

Animal model of therapeutic target

ADME, formulation, acute toxicology
The life history of a successful drug

12. Resource identification
Natural organisms, in particular plants
Medicinal plants continue to play a significant role
as a resource for the discovery of novel drugs
Balunas ad Koinghorn, Life Sci 2005.

13. • At least a quarter of all prescriptions dispensed in US
and UK contain, as active compounds, molecules derived
from flowering plants
• Medicines from natural sources are estimated to
comprise 80% of the medication used in primary
healthcare
• 12 out of the top 25 highest earning drugs are derived
from natural products

14. Ethno botanical approach
• Systematic screening of:
- Published literature on traditional medicinal plant use
(e.g. documented traditional healers‘ experience)
- Historical texts (e.g. ancient botanico-medicinal
manuscripts)
Advantages:
Pre-selection of potentially active resources
Promising safety profile (age-long experience)
Cost-efficient and comparatively fast

15. Drug Discovery
One way to “discover” drugs

16. Serendipitous Drug Discovery
• The use of nitrous oxide and ether as narcotic gases in
surgery resulted from the observation that people who
inhaled these chemicals [in parties] did not experience any
pain after injury.
• The vasodilatory activity of amyl nitrite and nitroglycerin was
discovered by chemists who developed strong headaches
after inhaling or ingesting minor amounts.
• Acetylsalicylic acid was thought to be just a better tolerable
prodrug of salicylic acid, but turned out to have a unique
mechanism.
• Phenolphthalein was considered as a useful dye for cheap
wines; after a heroic self-experiment, a pharmacologist
experienced its drastic diarrhoic activity.
• Warfarin was used a rat poison.

17. Combinatorial chemistry
• Medicinal Chemists want to find a new medicine
that is more effective than an existing one, or
causes fewer side effects
• This can be achieved by synthesis of analogues
• Combinatorial chemistry is a synthetic strategy that
leads to large number of similar compounds in a
short period of time.
• The compounds that are generated are analogues
of compounds that are already biologically active

18. Combinatorial Chemistry approaches
• Solid-Phase Organic Synthesis:
The compound library have been synthesized on solid phase such
as resin bead, pins, or chips
• Solution-Phase Organic Synthesis
The compound library have been synthesized in solvent in the
reaction flask

19. Solid Phase Synthesis
 Product is linked to a Solid Support:
 Easy purification - Easy removal of excess reagents through
filtration
 Low yield

20. A simple model
1. Take some beads made from a polymer
2. React the beads with a group called a linker
3. Mix the bead in with an alcohol that you
want to use in a chemical reaction. The
linker will bind to it and hold it on the bead.

21. Cont’d
4. Have 6 reaction vessels each containing a
different acyl chloride. Put a 1/6 of your
beads into a mesh bag and put into a
container.

22. Cont’d
5. Esterification occurs forming 6 different esters.
6. The beads are removed from the vessel by lifting
up the mesh bag. They are washed to remove any
unreacted acyl chloride

23. Cont’d
7. A reaction is used to break the linker group
down.
8. The polymer beads are reused
9. You have made 6 different esters which
can now be tested for biological activity

24. Advantage??????
Large numbers of similar compounds have
been synthesised in a very short period
of time. Imagine how much longer it would
take if you did the reaction with one alcohol
and acyl chloride, and then did it again with a
different acyl chloride, and then again,
and again…. 36 times!

25. Combinatorial Chemistry
The game with the large numbers !!!

26. High throughput screening for drug
discovery
• FACT 1: recent understanding of disease
mechanisms (genomics era) has dramatically
increased no. of protein targets for new drug
treatment
• FACT 2: new technologies (e.g combinatorial
chemistry) have increased the number of drugs
that can be tested for activity at these targets.

27. HTS for drug discovery
• HTS is process by which large numbers of compounds are rapidly
tested for their ability to modify the properties of a selected
biological target.
• Goal is to identify ‘hits’ that:
 affect target in desired manner
 active at fairly low concentrations (i.e more likely to show
specificity)
 new has a new structure
• The greater the no. and diversity of compounds screened, the
more successful screen is likely to be.
• HTS = 50,000-100,000 compounds screened per day!!!

28. HTS
• The majority of drug targets are :
G-protein coupled 7 TM receptors (approx. 5000), nuclear
receptors(>150), ion channels (Approx. 1000), Enzymes
(Approx. total uncertain)
• For instance, for the top 100 drugs
18 bind to GPCR, 10 bind to nuclear receptors, 16 bind to ion
channels and most of remainder inhibit enzymes
• HTS can be used to screen for activity at all of these targets
to determine activity
 potency
 specificity, if screen simultaneously against different targets

29. Implementation of HTS: Needs
1. suitable libraries of compounds
• Source of chemicals for screen:
- in-house collection (5x105
- 106
) of diverse
samples.
- supplement by acquisitions from specialist
companies
- combinatorial chemistry allows synthesis of large
no of diverse molecules.

30. Cont’d
2. assay method configured for automation
Assay requirements:
a) pharmacology of the target should not be altered by the
molecular manipulations
b) cost of assay development and reagents low
c) easy to use and suitable for automation ; assay requiring
few manipulations, no plate-o-plate transfers or washing
steps
d) robust signal-to-noise ratio. Hit defined as activity above a
certain threshold e.g. Ki < 5 nM

31. HTS Assays
• Radio-ligand binding assay: Measures affinity of
library compounds for target
• Cell-based fluorescence and radiotracer assays:
Useful for measuring ion-channel function
• Cell viability assays
• Cell proliferation assays
• Etc.

32. Needs cont’d
3) robotics workstation: Robots handle assays
in multi-well formats.
- sample dilutions
- sample dispensing
- plate washing

33. Cont’d
4) computerised data handling system
•A great deal of data is generated. Must be
accurate and reproducible.
• Need good computerised data handling
systems.

34. Combinatorial chemistry-HTS

35. Virtual screening
• Goal: identify ligands that tightly bind to a
protein
• Requirements: a computer database of
random potential ligands and a structure of
the target protein
• Repetitively dock new ligands to protein
• Score how tightly each ligand may bind
• Keep best ‘hits’; discard other ligands

36. Virtual
Sreening
Database
Experimental
Tests
Hits
N
OH
N
OH
N
OH
O
COOH
Br
Screening and hits selection
QSPR model
Useless
compounds
O
Cl
COOH
Br

37. Methodologies of a virtual screening
from A.R. Leach, V.J. Gillet “An Introduction to Chemoinformatics”, Kluwer Academic Publisher, 2003

38. Main Classes of Virtual Screening Methods
• Depend on the amount of structural and bioactivity
data available
– One active molecule known: perform similarity search
(ligand-based virtual screening)
– Several active molecules known: try to ID a common 3D
pharmacophore, then do a 3D database search
– Reasonable number of active and inactive structures
known: train a machine learning technique
– 3D structure of the protein known: use protein-ligand
docking

39. Platform for Ligand Based Virtual Screening
• Similarity search
~106
– 109
molecules
~103 -
– 104
molecules
Candidates for docking or
experimental tests
• Filters
• QSAR models

40. Filters to estimate “drug-likeness”

41. Lipinski rules for intestinal absorption
(« Rules of 5 »)
• H-bond donors < 5
(the sum of OH and NH groups);
• MWT < 500;
• LogP < 5
• H-bond acceptors < 10
(the sum of N and O atoms without H attached).

42. Lipinski rules for drug-like molecules (« Rules of 5 »)

43. Remove compounds containing too many rings

44. Remove compounds with toxic groups

45. Remove compounds with reactive groups

46. References
• Foye’s principles of medicinal chemistry
• Fundamentals of medicinal chemistry by
Gareth Thomas
• Medicinal chemistry by Ashutosh Kar 4th
Ed