WELCOME

INTRODUCTION TO

DRUG DESIGN AND

DISCOVERY

ANU SMPHARM PART IPHARMACEUTICAL CHEMISTRY

INTRODUCTION

DRUG DISCOVERY - Finding a

lead

DRUG DESIGN

CONCLUSION

REFERENCES

CONTENTS

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

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

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

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.

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

Targeting drugs to specific organs and tissues

Eg:- β1 and β2 receptors in heart and lungs

Pitfalls Eg:- Metachlorpromide (D2 antagonist),

Ondansterone (5HT antagonist)

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

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

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

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.

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

If the lead compound is present in a mixture

of other compounds it has to be isolated and

purified

5. Isolation and purification

X-Ray crystallography

NMR spectroscopy.

6. Structure determination

Optimizing target interactions

Optimizing access to the target

DRUG DESIGN

Identify structure activity relationships

(SARs)

Identify the Pharmacophore

Drug optimization: strategies in drug

design

DRUG DESIGN – Optimizing target interactions

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

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

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

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

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.

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

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

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

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.

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

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.

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

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

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

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

1. An introduction to Medicinal Chemistry – Graham L Patrick

2.http://www.phrma.org/sites/default/files/159/ rd_brochure_022307.pdf

REFERENCES