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

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.

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

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.

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.

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

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)

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

Structure-based Drug Design

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)

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

Aspirin substitutes

Antihistamines

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

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

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

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

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)

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

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