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Premium member Presentation Transcript PowerPoint Presentation: Structure-based Drug DesignPain relievers: aspirin: Pain relievers: aspirin Analgesic (pain reliever) Antipyritic (fever reducer) Anti-inflammatory Anticoagulent Inhibits production of prostaglandins (pain messengers) 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 patentAntibacterial drugs: penicillins: Antibacterial drugs: penicillins 1941 Prevents crosslinking between proteins and therefore cell wall synthesis (mucoproteins).Aspirin substitutes: Aspirin substitutes Now banned Tylenol Advil Aleve Orudis KTAntihistamines: AntihistaminesAntibacterial drugs: sulfa drugs: Antibacterial drugs: sulfa drugs Chemical mimic-type poison for bacteria 1935Other antibacterial drugs: Other antibacterial drugs Fluoroquinolone bind to bacterial ribosomes inhibits bacterial DNA replicationPowerPoint Presentation: 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 approvalPowerPoint Presentation: Drugs derived from structure-based approaches Nelfinavir in the active site of HIV-1 protease: Agouron's AIDS drug nelfinavir (brand name Viracept) is one of the drugs on the market that can be traced directly to structure-based methods.PowerPoint Presentation: 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 1999 Gilead and Roche Gleevec Imatinib BCR- Abl Chronic myelogenous leukaemia 2001 Novartis Drugs derived from structure-based approachesPowerPoint Presentation: Determination of Target Structure Crystal structure of Rhodopsin: A G protein-coupled receptor. Palczewski et al . Science (2000) 289 , 739- 45.PowerPoint Presentation: A. Binding site comprising three binding pockets B. Crystallographic screening locates molecular fragments that bind to one, two or all three pockets C. A lead compound is designed by organizing all three fragments around a core template D. Growing out of a single fragmentExample Combinatorial Library: Example Combinatorial Library NH R1 R2 R3 Scaffold “R”-groups R1 = OH OCH 3 NH 2 Cl COOH R2 = phenyl OH NH 2 Br F CN R3 = CF 3 NO 2 OCH 3 OH phenoxy Examples NH OH CN OH NH OH O CH 3 NH C OH OH O CF 3 NH C OH OH O O For this small library, the number of possible compounds is 5 x 6 x 5 = 150PowerPoint Presentation: Lead Identification by Fragment EvolutionSimilarity Paradox: Similarity ParadoxDescriptors of Molecular Structure & Properties: Descriptors of Molecular Structure & Properties 1D-descriptors encode chemical composition & physicochemical properties MW, C m O n H k ,hydrophobicity 2D-descriptors encode chemical topology Connectivity indices, degree of branching, degree of flexibility, # of aromatic bonds 3D-descriptors encode 3D shape, volume, functionality, surface area Pharmacophore – the spatial arrangement of chemical groups that determines its activityLipinski Rule of Five (1997): Lipinski Rule of Five (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 activityIn Silico ADME Models: In Silico ADME Models Computational methods can predict compound properties important to ADME, e.g. LogP, a liphophilicity measure Solubility Permeability Cytochrome p450 metabolism Means estimates can be made for millions of compouds, helping reduce “attrition” – the failure rate of compounds in late stagePowerPoint Presentation: Structure of Cytochrome P450: responsible for primary metabolism of majority of drugs in human body -likely to herald a new era of structure-based design in the modulation of metabolic properties of drugs. Can metabolism properties be modulated? You do not have the permission to view this presentation. In order to view it, please contact the author of the presentation.