Lead identification

Lead Indentification in Drug Discovery

1. Presented by: Vikram Choudhary
M. Pharm First Semester, School of Pharmacy, DAVV, Indore

2. Content of Presentation-
 Introduction
What is Lead ?
Properties of Lead
Methods of Lead Identification
Applications

3. Introduction
LEAD IDENTIFICATION
Disease Target
Drug Target
Lead Discovery
Lead Modification
Preclinical & Clinical
Development
Regulatory Approvals

4. LEAD IDENTIFICATION
• Once a target & a testing system has been chosen, the next is
to find a “Lead Compound” which shows the desired
pharmaceutical activity.

•A lead compound is generally defined as a new chemical
entity that could potentially be developed into a new drug by
optimizing its beneficial effects and minimizing its side effects.

What is Lead ?

5. LEAD IDENTIFICATION
• Lead compounds are typically used as starting points in the drug
design to give new drug entities.
•Drug Design strategies can be used to improve the compound’s
pharmacodynamic and pharmacokinetic properties.
• The resulting compounds from drug design go through a series of
preclinical studies and become clinical candidates if the compounds
don’t exhibit adverse effects or toxicity during in vitro and in vivo studies.
• After going through marketing obstacles and clinical trials, compounds
that pass are released in the market as new deug entities.
What is Lead ?
Cont’d

6. • New drug entities are generally monitored for safety after their
released on the market.
•Possible Source of Lead Compounds and Novel drugs include-
1. Endogenous Ligands-
i.e.- Substrate for enzyme and transportersor agonist for
receptors
Cont’d
LEAD IDENTIFICATION
What is Lead ? N
H
NH
2
HO
Serotonin HO
HO
Ac
OH
Norepinephrine

7. LEAD IDENTIFICATION
What is Lead ?
2. Natural Products 2. Natural Products

8. Cont’d
LEAD IDENTIFICATION
What is Lead ?
3. Animals
Animal cartilage
Gelatin capsules or gummy vitamins chondroitin
 Animal bones
Calcium
Animal blood
Heme iron

9. Cont’d
LEAD IDENTIFICATION
What is Lead ?
4. Microorganisms
Penicillin

10. Cont’d
LEAD IDENTIFICATION
What is Lead ?
5. Chemical Libraries (Such as Combinatorial Chemistry)
6. Computational Medicinal Chemistry

11. Properties of Lead
LEAD IDENTIFICATION
 Pharmacodynamic Properties –
 Efficacy,
 Potency,
 Selectivity
 Physiochemical Properties –
 Water solubility,
 Chemical stability
 Pharmacokinetic Properties –
 Metabolic stability
 Toxological aspects.

12. LEAD IDENTIFICATION
 Chemical Optimization Potential –
 Ease of chemical synthesis and
derivatization.
 Patentability
Cont’d
Properties of Lead

13. LEAD IDENTIFICATION
• During the early stages of drug discovery for a certain
disease, the underlying molecular mechanism behind the
disease are studied.
Organic compounds are identified which interact with
the target protein and modulate its activity by using
random (screening) or rational (design) approaches.
Cont’d
Properties of Lead

14. LEAD IDENTIFICATION
Random Screening
Nonrandom Screening
High-Throughput Screening
Structure based drug design
Methods of Lead Identification

15. Cont’d
LEAD IDENTIFICATION
This method was followed before 1970.
All compounds including synthetic chemicals, natural
products of plant, marine and microbial origin from a given
series are tested.
 Inspite of budgetary and manpower overuse, this method
may be used to discover drugs or leads that have unexpected
activities.
Antibiotics like, streptomycin and tetracyclines were found
out by this method.
Methods of Lead Identification
Random or Targeted Screening Method

16. LEAD IDENTIFICATION
Cont’d
Methods of Lead Identification
Non-Random Screening Method
 After 1970 this method used.
It is a modified form of random screening which
was developed because of budgetary and manpower
restrictions.
 In this method, only such compounds having
similar structural skeletons with that of lead, are
tested.

17. LEAD IDENTIFICATION
High-Throughput Screening
 Test thousands of compounds against the target to
identify any that might be promising natural product and
synthetic compound libraries with millions of
compounds are screened using a test assay.
 In theory generating the entire ‘chemical space’ for
drug molecules and testing them would be an elegant
approach to drug discover
Methods of Lead Identification
Cont’d

18. LEAD IDENTIFICATION
Structure Based Drug Design
 Three dimensional structures of compounds from virtual or
physically existing libraries are docked into binding sites of
target proteins with known or predicted structure.
 Scoring functions evaluate the steric and electrostatic
complementarity between compounds and the target protein.
 The highest ranked compounds are then suggested for
biological testing.
Cont’d
Methods of Lead Identification