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Drug Discovery Process by Kashikant Yadav

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Drug Discovery Process: Lead Identification and Lead Optimization

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Drug Discovery Process by Kashikant Yadav

  1. 1. AN OVER VIEW OF MODERN DRUG DISCOVERY PROCESS: LEAD IDENTIFICATION AND LEAD OPTIMIZATION Kashikant Yadav M Pharmacy(pharmacology) KarnatakaCollege of pharmacy
  2. 2. Drug Discovery and Drug development  drug discovery is the process by which new candidate medications are discovered  Drug development is the process of bringing a new pharmaceutical drug to the market once a lead compound has been identified through the process of drug discovery
  3. 3. Lead compound  chemical compound that has pharmacological or biological activity likely to be therapeutically useful  Also called developmental candidates, because the discovery and selection of lead compounds occurs prior to preclinical and clinical development of the candidate.
  4. 4. criteria for leads  Pharmacodynamic properties - efficacy, potency, selectivity  Physiochemical properties - water solubility, chemical stability  Pharmacokinetic properties - metabolic stability and toxological aspects.  Chemical optimization potential - ease of chemical synthesis and derivatization.  Patentability
  5. 5. Lead Identification  Organic compounds are identified which interact with the target protein and modulate its activity by using random (screening) or rational (design) approaches.
  6. 6. High-throughput Screening  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
  7. 7. 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.
  8. 8. Methods of lead Identification I)Random screening:  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.
  9. 9. ii) Nonrandom screening:  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.
  10. 10. iii) Drug metabolism studies :  Structural modifications are done in drug molecule by the enzymes to increase its polarity.The discovery of sulfanilamide is reported through the metabolic studies of prontosil.
  11. 11. iv) Clinical observations:  Many times the drug possesses more than one pharmacological activities.The main activity is called as therapeutic effect while rest of the actions is known as side effects of the drug.  Such drug may be used as lead compound for structural modifications to improve the potency of secondary effects.
  12. 12. Rational approaches to lead discovery  The knowledge about the receptors and their mode of interaction with drug molecules plays an important role in drug design.  This knowledge may be used to develop conformationally bioactive skeletons having exact three-dimensional complementarity to a receptor.
  13. 13.  Greater potency, higher selectivity and less adverse effects are expected by reducing the flexibility of the drug structure.  This approach is of greater importance in identification of lead nucleus.  It involves the use of signs and symptoms of the disease.
  14. 14. Lead Optimization  Molecules are chemically modified and subsequently characterized in order to obtain compounds with suitable properties to become a drug.  Leads are characterized with respect to pharmacodynamic properties such as efficacy and potency in vitro and in vivo, physiochemical properties, pharmacokinetic properties, and toxicological aspects.  Once compounds with desirable in vitro profiles have been identified, these are characterized using in vivo models
  15. 15. Charaterizing Leads  Potency refers to the amount of drug required for its specific effect to occur  Efficacy measures the maximum strength of the effect itself,at saturating drug concentrations.  Pharmacokinetics - “what the body does to the drug.”  Pharmacodynamics –  determining the biochemical and physiological effects of drugs  the mechanism of drug action and  the relationship between drug concentration and effect.
  16. 16.  Lead optimization requires the simultaneous optimization of multiple parameters and is thus a time consuming and costly step.
  17. 17. Methods of Lead Optimization in Analog Design 1. Identification of the active part (Pharmacophore). 2. Functional group optimization. 3. Structure activity relationship studies. 4. Bioisosteric replacement. 5. Design of rigid analogs.
  18. 18. 6. Homologation of alkyl chains or alteration of chain branching, design of aromatic ring position isomers, alteration of ring size, and substitution of an aromatic ring for a saturated one or the converse. 7. Alteration of stereochemistry, or design of geometric isomers or stereoisomers. 8. Design of fragments of the lead molecule that contain the pharmacophoric group (bond disconnection). 9. Alteration of interatomic distances within the pharmacophoric group or in other parts of the molecule.