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Lead Series

Biological Discovery. Biodisposition. High Volume Screening. Toxicity. IND. Lead Series. Combinatorial Diversity. Efficacy. Rational [Structure, Design, Informatics]. Pharmacokinetics. Iterative Process. Preclinical R&D. Lead Discovery Research. Rational Drug Discovery.

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Lead Series

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  1. Biological Discovery Biodisposition High Volume Screening Toxicity IND Lead Series Combinatorial Diversity Efficacy Rational [Structure, Design, Informatics] Pharmacokinetics Iterative Process Preclinical R&D Lead Discovery Research Rational Drug Discovery • Full Toolbox Required to Compete Successfully MEDC 607 & MEDC 603

  2. Rational Drug Discovery • Definition • Rational – Reason-based • Not based on chance alone • May not involve computers • Types of Drug Discovery Searches • Structure – based Drug Design (structure of the receptor, binding site, AA residues, thermodynamics) • Pharmacophore – based Drug Design (structure of the ligand, SAR, QSAR) • Mechanism – based Drug Design (molecular mechanism of action, transition state) MEDC 607 & MEDC 603

  3. Receptor-based Drug Design • Design of Antithrombin Activators MEDC 607 & MEDC 603

  4. _ _ _ _ _ _ _ _ _ _ Receptor-based Drug Design • Binding Site Information Arg47 Lys114 Lys125 Arg46 Arg129 Asn45 Arg13 Lys11 MEDC 607 & MEDC 603

  5. Receptor-based Drug Design • Thermodynamics -DGO (kcal/mol) MEDC 607 & MEDC 603

  6. Receptor-based Drug Design • Computerized Modeling MEDC 607 & MEDC 603

  7. A) B) 2 3 DEF = ECS = ECS = (2S,3S) (+)CS = (2S,3R) HINT Score Pentasaccharide Binding Site Residues MoS :: R = H, R’ = OSO3- QS :: R = OSO3-, R’ = H Receptor-based Drug Design • Design of New Structures MEDC 607 & MEDC 603

  8. Levorphanol (a morphinan) Pentazocine Morphine R = R’ = H Codeine R = Me, R’ = H Heroin R = R’ = COCH3 (3 – 4X morphine analgesic + retains additive property) (less potent than morphine + reduced additive property) (Analgesic + additive) Methadone Meperidine (equipotent as morphine analgesic + almost no additive) (10-12% of morphine analgesic + much lowered additive) (less potent than morphine + reduced additive property) Pharmacophore-based Drug Design • Natural Product Derivatization and Pharmacophore Elucidation MEDC 607 & MEDC 603

  9. + _ _ _ _ _ _ _ Mechanism-based Drug Design • Design of HIV Protease Inhibitor Mechanism of Aspartic Proteinases MEDC 607 & MEDC 603

  10. Mechanism-based Drug Design IC50 (nM) Inhibitor Structure HIV-1 HIV-2 Z.Phe[CH(OH)CH2N]Pro.OtBu 6,500 Z.Asn.Phe[CH(OH)CH2N]Pro.OtBu 140 330 Z.Asn.Phe[CH(OH)CH2N]Pro.OtBu 300 MEDC 607 & MEDC 603

  11. Rational Design of HIV-1/2 Proteinase Inhibitors IC50 (nM) Inhibitor Structure HIV-1 HIV-2 Z.Leu.Asn.Phe[CH(OH)CH2N]Pro.Ile.NHiBu 750 Z.Asn.Phe[CH(OH)CH2N]Pro.NHiBu 210 Z.Asn.Phe[CH(OH)CH2N]PIC.NHiBu 18 MEDC 607 & MEDC 603

  12. Rational Design of HIV-1/2 Proteinase Inhibitors IC50 (nM) Inhibitor Structure HIV-1 HIV-2 QC.Asn.Phe[CH(OH)CH2N]PIC.NHiBu 2 9.5 QC.Asn.Phe[CH(OH)CH2N]DIQ.NHiBu <0.4 <0.8 MEDC 607 & MEDC 603

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