Introduction

1. Rational Drug DesignDr 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

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) File IND Preclinical testing (1-3 years) File NDA Formulation 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….. !!