Rational Drug Discovery

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Presentation transcript:

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

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

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

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

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

Receptor-based Drug Design Computerized Modeling MEDC 607 & MEDC 603

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

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

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

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

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

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