1. Rational Drug Design Dr SANTOSH MOKALE. Professor,
Rational Drug Design Dr SANTOSH MOKALE Professor, Dept of Pharmaceutical Chemistry, Y. B. Chavan College of Pharmacy, Aurangabad

2. Introduction
Drug: Compounds used for the prevention and treatment of diseases and disorder
Ideal drug:
1) target: bio-molecule ,involved in signaling or metabolic pathways, that are specific to disease.
2) antagonist action-inhibiting functions of the disease causing proteins.
3) Inhibiting interactions of the proteins.
4) Activates other proteins, that are deregulated in such disease like cancer.

3. Drug designing is: 1) Challenging 2) Expensive 3) Time consuming
So, Multidisciplinary approach:
Computational tools, methodologies for structure guided approach.
Hence,
Efficiency increased
Cost effectiveness
Time saved
Strategies to overcome toxic side effects

4. Drug Design
2 ways:
Development of ligands with desired properties for targets having known structure and functions.
Development of ligands with predefined properties for targets whose structural information may be or may not be known.

5. Important Points in Drug Design
History of Drug/Vaccine development
Plants or Natural Product
Plant and Natural products were source for medical substance
Example: foxglove used to treat congestive heart failure
Foxglove contain digitalis and cardiotonic glycoside
Identification of active component
Accidental Observations
Penicillin is one good example
Alexander Fleming observed the effect of mold
Mold(Penicillium) produce substance penicillin
Discovery of penicillin lead to large scale screening
Soil micoorganism were grown and tested
Streptomycin, neomycin, gentamicin, tetracyclines etc.

6. Important Points in Drug Design
Chemical Modification of Known Drugs
Drug improvement by chemical modification
Pencillin G -> Methicillin; morphine->nalorphine
Receptor Based drug design
Receptor is the target (usually a protein)
Drug molecule binds to cause biological effects
It is also called lock and key system
Structure determination of receptor is important
Ligand-based drug design
Search a lead ocompound or active ligand
Structure of ligand guide the drug design process

7. Important Points in Drug Design
Identify Target Disease
Identify and study the lead compounds
Marginally useful and may have severe side effects
Refinement of the chemical structures
Detect the Molecular Bases for Disease
Detection of drug binding site
Tailor drug to bind at that site
Protein modeling techniques
Traditional Method (brute force testing)

8. Lipinski Rule (1997)
Poor absorption and permeation are more likely to occur when there are more than 5 hydrogen-bond donors, more than 10 hydrogen-bond acceptors, the molecular mass is greater than 500, or the log P value is greater than 5.
Further research studied a broader range of physicochemical and structural properties.
Related problems:
Compound toxicity
Compound mutagenicity
Blood-brain barrier penetration
Central nervous system activity

9. Structure-based Drug Design

10. Pain relievers: Aspirin
Analgesic (pain reliever)
Antipyritic (fever reducer)
Anti-inflammatory
Anticoagulent
History of Aspirin
Hippocratus: powder made from the bark and leaves of the willow tree to help heal headaches, pains and fevers
Henri Leroux & Raffaele Piria: purification of active ingradient from the plant
1899 Hoffman: formulation and patent
Inhibits production of prostaglandins (pain messengers)

11. Antibacterial drugs: Penicillins
1941
Prevents crosslinking between proteins
and therefore cell wall synthesis (mucoproteins).

12. Aspirin substitutes

13. Antihistamines

14. Antibacterial drugs: Sulfa drugs
1935
Chemical mimic-type poison for bacteria

15. Other Antibacterial Drugs
Fluoroquinolone
Bind to
bacterial
ribosomes
Inhibits
bacterial DNA
replication

16. Structure-based Drug Design Cycle
Target identification and validation
Assay development
Virtual screening (VS)
High throughput screening (HTS)
Quantitative structure – activity relationship (QSAR) and refinement of compounds
Characterization of prospective drugs
Testing on animals for activity and side effects
Clinical trials
FDA approval

17. Drugs derived from structure-based approaches
Capoten
Captopril
ACE
Hypertension
1981
Bristol-Myers Squibb
Trusopt
Dorzolamide
Carbonic anhydrase
Glaucoma
1995
Merck
Viracept
Nelfinavir
HIV protease
HIV/ AIDS
1999
Agouron (Pfizer) and Lilly
Tamiflu
Oseltamivir
Neuraminidase
Influenza
Gilead and Roche
Gleevec
Imatinib
BCR- Abl
Chronic myelogenous leukaemia
2001
Novartis

18. Drug Discovery & Development
Identify disease
Find a drug effective
against disease protein
(2-5 years)
Isolate protein
involved in
disease (2-5 years)
Scale-up
Human clinical trials
(2-10 years)
Preclinical testing
(1-3 years)
File IND
Formulation
File NDA
FDA approval
(2-3 years)

19. Techology is impacting this process
GENOMICS, PROTEOMICS & BIOPHARM.
Potentially producing many more targets
and “personalized” targets
HIGH THROUGHPUT SCREENING
Identify disease
Screening up to 100,000 compounds a
day for activity against a target protein
VIRTUAL SCREENING
Using a computer to
predict activity
Isolate protein
COMBINATORIAL CHEMISTRY
Rapidly producing vast numbers
of compounds
Find drug
MOLECULAR MODELING
Computer graphics & models help improve activity
Preclinical testing
IN VITRO & IN SILICO ADME MODELS
Tissue and computer models begin to replace animal testing

20. THANK YOU….. !!