This document provides an introduction to drug design and discovery. It discusses finding a lead compound through screening natural products, existing drugs, and synthetic compound libraries. Once a lead is identified, its structure is determined using techniques like X-ray crystallography and NMR spectroscopy. The lead is then optimized for target interactions and access to the target through strategies like structure-activity relationships, pharmacophore identification, and prodrug design. Drug design aims to improve properties like absorption, resistance to degradation, toxicity reduction, and targeting to specific sites. Developing new drugs is a lengthy process built upon past failures and advances in biological understanding.

1. WELCOME

2. INTRODUCTION TO
DRUG DESIGN AND
DISCOVERY
ANU S
MPHARM PART I
PHARMACEUTICAL
CHEMISTRY

3. INTRODUCTION
DRUG DISCOVERY - Finding a
lead
DRUG DESIGN
CONCLUSION
REFERENCES
CONTENTS

4. Ancient times – medicines were herbs and poisons
Serious efforts were made to isolate and purify the
active principles - after the mid-nineteenth century.
A large variety of biologically active compounds were
obtained and structures determined (e.g. morphine,
cocaine, quinine etc.)
Natural products became the lead compounds
No real design or reason.
INTRODUCTION

5.  Choose a disease
 Choose a drug target
 Identify a bioassay
 Find a lead compound
 Isolate and purify the lead compound
 Determine the structure of the lead
compound
DRUG DISCOVERY
Finding a Lead

6. Pharmaceutical companies tend to avoid
products with a small market
Avoid products for individuals of lower
economic status
Most research is carried out on diseases which
afflict “first world” countries
1. Choosing a Disease

7. Understand the disease and identify cause of the
condition.
Understand how the genes are altered and how
that affects the proteins they encode.
Choosing a Disease contd.

8. Drug Targets
Discovering drug targets
Target specificity and selectivity between
species, Eg:- Pencilin targets only bacterial cells
but not mammalian cells.
Target specificity and selectivity within the body,
Eg:- Specific enzyme inhibitors.
2. Choosing a Drug Target

9. Targeting drugs to specific organs and tissues
Eg:- β1 and β2 receptors in heart and lungs
Pitfalls Eg:- Metachlorpromide (D2 antagonist),
Ondansterone (5HT antagonist)

10. Choice of bioassay
In vitro tests
In vivo tests
Test validity
High-throughput screening
Screening by NMR
Affinity screening
Surface Plasmon resonance
Scintillation proximity assay
3. Identifying a bioassay

11. a) Screening of natural products
The plant kingdom
The microbial world
The marine world
Animal sources
Venoms and toxins
b) Medical folklore
4. Finding a lead compound

12. c) Screening synthetic compound libraries
d) Existing drugs
‘Me too’ drugs Eg:- Captopril
Enhancing a side effect, Eg:- Sulfonamides & sulfonyl
ureas
e) Starting from the natural ligand or modulator
Natural ligands for receptors – Adrenalin, nor
adrenalin
Natural substrates for enzymes - enkephalins

13. Enzyme products as lead compounds – Product of an
enzyme catalysed reaction –
L-benzyl succinic acid (Carboxypeptidase catalysed
hydrolysis)
Natural modulators as lead compounds
f) Combinatorial synthesis
It is an automated solid phase procedure aimed at
producing as many different structures as possible in as
short a time as possible.

14. g) Computer aided design
h) Serendipity and the prepared mind
Eg: Cisplatin, Ampicillin
i) Computerised searching for structural database
Database mining
j) Designing lead compounds by NMR

15. If the lead compound is present in a mixture
of other compounds it has to be isolated and
purified
5. Isolation and purification

16.  X-Ray crystallography
 NMR spectroscopy.
6. Structure determination

17. Optimizing target interactions
Optimizing access to the target
DRUG DESIGN

18. Identify structure activity relationships
(SARs)
Identify the Pharmacophore
Drug optimization: strategies in drug
design
DRUG DESIGN – Optimizing target
interactions

19. The aim here is to discover which parts of the
molecule are important to biological activity and
which are not.
It is important to identify the binding roles of
different groups.
Structure activity relationships

20. The pharmacophore summarizes the
important binding groups which are
required for activity and their relative
positions in space with respect to each
other.
Identification of a pharmacophore

21. Variation in substituents
Alkyl substituents- Adrenaline,methyl group
substituted with isopropyl gives isoprenaline
Aromatic substitutions- Benzopyran substituted
with sulfonamides,increases antiarrythmic activity
Extension of the structure
Chain extension/contraction Eg:- Pencillin
Drug optimization: Strategies in
drug design

22. Ring expansion/contraction – CilazaprilAt
synthesized from captopril
Ring variations – Most of the NSAIDs are
variables of 1,2 biaryl system.
Ring fusions – Adrenaline and napthalene gives
pronethalol
Isosteres and bioisosteres – Uracil and 5 fluro
uracil

23. Simplification of the structure – Cocaine &
Procaine
Rigidification of the structure – Diazepine binds
with target group guanidine by a flexible chain
when it is rigidified activity increases
Conformational blockers – Substitution may
decreases rotation of single bond and decreases
activity eg:- substitution of CH3 in dopamine.

24. X-Ray crystallography
 Drug design by NMR
 The elements of luck and inspiration – Discovery
of propranolol from pronethalol
Structure based drug design and molecular
modelling

25. 1. Improving absorption
Variation of alkyl or acyl substituents to vary
polarity – Introduction of alkyl group in sildenafil
increases absorption.
Varying polar functional groups to vary polarity –
Tioconazol only use in skin infections because of
its non polar solubility to blood
DRUG DESIGN – Optimizing
access to the target

26. Variation of N-alkyl substituents to vary pKa –
Increase in number of alkyl group increases
stearic bulk around N2 and decreases
absorption
Variation of aromatic substituents to vary pKa
– Done by adding electron withdrawing groups
Bioisosteres for polar groups – Carboxylic acid
(highly polar group) used to drcrease absorption

27. 2. Making drugs more resistant to
chemical and enzymatic degradation
Steric shields – N butyl groups
Electronic effects of bioisosters – Substitution of
methyl group with amino group in ethanolic esters.
Metabolic blockers
Megesterol acetate oxidise at 6th position form
hydroxy group,when flurine is substituted prevent
oxidation.

28. Removal of susceptible metabolic groups –
Aromatic methyl substitution of tolbutamine
replaced by chlorine to give chlorpropamide
Group shifts – Salbutamol and adrenaline
Ring variation – Imidazol ring of tioconazole
replaced with 1,2,4 – triazol gives fluconazole

29. 3. Making drugs less resistant to drug
metabolism
Introducing metabolically susceptible groups –
Renifentanil substituted with ester group
decrease metabolism
Self destruct drugs – Atracurium stable in acid
pH but unstable in basic pH.

30. 4. Targeting drugs
Targeting tumour cells - ‘search and destroy
drugs’ – Monoclonal antibodies
Targeting gastrointestinal tract infections –
Done by producing fully ionized drugs eg:-
Sulfonamides
Targeting peripheral regions rather than CNS –
These drugs used to decrease CNS side effects

31. 5. Reducing toxicity
6. Prodrugs
Prodrugs to improve membrane permeability- enalapril 
enalaprilat
Prodrugs to prolong drug activity
Azathioprine 6-mercaptopurine
Prodrugs masking drug toxicity and side effects
Aspirin salicylic acid
Prodrugs to lower water solubility
Palmitate ester of Chloramphenicol

32. 7. Drug alliances
Some drugs are found to affect the activity or
pharmacokinetic properties of other drugs
‘Sentry’ drugs
Use of a second drug to assist – Clavulanic acid
with penicillins
Localizing a drug’s area of activity
Procaine with adrenaline
Increasing absorption
Metoclopramide with analgesics

33. The discovery and development of new
medicines is a long, complicated process.
Each success is built on many, many prior
failures.
 Advances in understanding human biology
and disease are opening up exciting new
possibilities for breakthrough medicines.
CONCLUSION

34. 1. An introduction to Medicinal Chemistry – Graham L Patrick
2.http://www.phrma.org/sites/default/files/159/ rd_brochure_022307.pdf
REFERENCES