drug design and discovery
TRANSCRIPT
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