3D_LECTURE_2005_3
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Jürgen Sühnel Jürgen Sühnel [email protected] [email protected] Institute of Molecular Biotechnology, Jena Centre for Bioinformatics Institute of Molecular Biotechnology, Jena Centre for Bioinformatics Jena / Germany Jena / Germany Supplementary Material: http://www.imb-jena.de/www_bioc Structures of Biological Macromolecul Structures of Biological Macromolecul Part 3 Part 3 Drug Research and Design Drug Research and Design
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Transcript of 3D_LECTURE_2005_3
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Jrgen [email protected] of Molecular Biotechnology, Jena Centre for BioinformaticsJena / GermanySupplementary Material: http://www.imb-jena.de/www_bioc/3D/3D Structures of Biological MacromoleculesPart 3Drug Research and Design
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Example of Drug Discovery
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Drug discovery Example of Drug Discovery
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Pacific yew tree(Eibe)Example of Drug Discovery
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Development of Drug Researchwww.kubinyi.de
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Drug Timelinewww.kubinyi.de
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Drug Timelinewww.kubinyi.de
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Drug Discovery Cost for discovering and developing a new drug: several 100 million up to 1000 million (average 802 M)
Time to market:10 15 years
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Costs in Drug Researchww.kubinyi.de
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Pharma Sales and Eearnings in 1999-2002ww.kubinyi.de
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The Worlds Top-Selling Drugs in 2004
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Disciplines Involved in Drug DevelopmentMolecular Conceptor
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The Role of Molecular StructureMolecular Conceptor
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The Pharmacophore ConceptMolecular Conceptor
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Mechanisms of Drug Action Definitions Iwww.kubinyi.de
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Mechanisms of Drug Action Definitions IIwww.kubinyi.de
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Serendipity - PenicillinMolecular Conceptor
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Serendipity - AspirinMolecular Conceptor
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Strateges in Drug Designwww.kubinyi.de
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3D Structures In Drug Researchwww.kubinyi.de
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Computational Approaches to Drug Discovery Target identification Lead discovery Lead optimization
Ligand-based design Receptor-based design (Docking)
Database screening (Virtual screening) Supporting combinatorial chemistry
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Lead Structure Identificationwww.kubinyi.de
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Lead Structure Searchwww.kubinyi.de
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Lead Structures: Endogeneous Neurotransmitterswww.kubinyi.de
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Lead Optimizationwww.kubinyi.de
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What is QSAR ?
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Basic Requirements in QSAR Studies
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QSARwww.kubinyi.de
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QSAR Parameterswww.kubinyi.de
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QSAR Parameters
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QSAR Parameters -Lipophilicity
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QSAR Parameterswww.kubinyi.de
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QSAR Parameterswww.kubinyi.de
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QSAR Parameterswww.kubinyi.de
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QSAR Parameterswww.kubinyi.de
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QSAR Parameterswww.kubinyi.de
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QSAR Parameterswww.kubinyi.de
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A QSAR Success Storywww.kubinyi.de
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A QSAR Success Storywww.kubinyi.depI50 concentration of test compound required to reduce the protein content of cell by 50%
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3D-QSAR - CoMFAwww.kubinyi.de
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Molecular Superposition of D Receptor Ligandswww.kubinyi.de
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The Future: Pharmagenomics and Personalized Medicinewww.kubinyi.de
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3D-QSAR - CoMFAwww.kubinyi.de
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3D-QSAR - CoMFAwww.kubinyi.de
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Electrostatic and Van-der-Waals Interactions
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Drug Discovery Ligand-based DesignComparativeMolecularField Analysis
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Hydrogen Bonds and Ligand Affinitieswww.kubinyi.de
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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Drug Discovery Receptor-based Design (Structure-based Design)
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Drug Discovery Receptor-based Design (Structure-based Design)
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Combinatorial Diversity in Naturewww.kubinyi.de
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Classical vs. Combinational Chemistryww.kubinyi.de
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Combinatorial Libraryww.kubinyi.de
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Combinatorial Libraryww.kubinyi.de
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Types and Features of Combinatorial Librariesww.kubinyi.de
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Virtual Screening: Select subsets of compounds for assay that are more likely to contain active hits than a sample chosen at random
Time Scales: Docking of 1 compound 30 s(SGI R10000 processor) Docking of the 1.1 million data set6 days (64-processor SGI ORIGIN)Virtual ScreeningACD-SC: Database from Molecular Design Ltd.Agonists: Known active compoundsDocking of ligands to the estrogen receptor (nuclear hormone receptor)
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Virtual Screening
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Lipinskis Rule of FiveCompounds are likely to have a good absorption and permeationin biological systems and are thus more likely to be successful drug candidatesif they meet the following criteria:
5 or fewer H-bond donors 10 or fewer H-bond acceptors Molecular weight less than or equal to 500 Calculated log P less than or equal to 5 Compound classes that are substrates for biological transporters are exceptions to the rule.
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ADME
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The Future: Pharmagenomics and Personalized Medicinewww.kubinyi.de
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Prediction Issueswww.kubinyi.de
