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Presented by: Vikram Choudhary
M. Pharm First Semester, School of Pharmacy, DAVV, Indore
Content of Presentation-
 Introduction
What is Lead ?
Properties of Lead
Methods of Lead Identification
Applications
Introduction
LEAD IDENTIFICATION
Disease Target
Drug Target
Lead Discovery
Lead Modification
Preclinical & Clinical
Development
Regulatory Approvals
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 ?
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
• 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
NH2
HO
Serotonin
HO
HO
Ac
OH
Norepinephrine
LEAD IDENTIFICATION
What is Lead ?
2. Natural Products2. Natural Products
Cont’d
LEAD IDENTIFICATION
What is Lead ?
3. Animals
Animal cartilage
Gelatin capsules or gummy vitamins chondroitin
 Animal bones
Calcium
Animal blood
Heme iron
Cont’d
LEAD IDENTIFICATION
What is Lead ?
4. Microorganisms
Penicillin
Cont’d
LEAD IDENTIFICATION
What is Lead ?
5. Chemical Libraries (Such as Combinatorial Chemistry)
6. Computational Medicinal Chemistry
Properties of Lead
LEAD IDENTIFICATION
 Pharmacodynamic Properties –
 Efficacy,
 Potency,
 Selectivity
 Physiochemical Properties –
 Water solubility,
 Chemical stability
 Pharmacokinetic Properties –
 Metabolic stability
 Toxological aspects.
LEAD IDENTIFICATION
 Chemical Optimization Potential –
 Ease of chemical synthesis and
derivatization.
 Patentability
Cont’dProperties of Lead
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
LEAD IDENTIFICATION
Random Screening
Nonrandom Screening
High-Throughput Screening
Structure based drug design
Methods of Lead Identification
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
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.
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
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
Lead identification

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Lead identification

  • 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 NH2 HO Serotonin HO HO Ac OH Norepinephrine
  • 7. LEAD IDENTIFICATION What is Lead ? 2. Natural Products2. 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’dProperties 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