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Jürgen Sühnel jsuehnel@imb-jena.de Institute of Molecular Biotechnology, Jena Centre for Bioinformatics Jena / Germany Supplementary Material: http://www.imb-jena.de/www_bioc/3D/ 3D Structures of Biological Macromolecules Part 3 Drug 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 Research www.kubinyi.de
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Drug Timeline www.kubinyi.de
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Drug Timeline www.kubinyi.de
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Drug Discovery 4 Cost for discovering and developing a new drug: several € 100 million up to € 1000 million (average € 802 M ) 4 Time to market: 10 – 15 years
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Costs in Drug Research ww.kubinyi.de
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Pharma Sales and Eearnings in 1999-2002 ww.kubinyi.de
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The World´s Top-Selling Drugs in 2004
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Disciplines Involved in Drug Development Molecular Conceptor
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The Role of Molecular Structure Molecular Conceptor
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The Pharmacophore Concept Molecular Conceptor
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Mechanisms of Drug Action – Definitions I www.kubinyi.de
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Mechanisms of Drug Action – Definitions II www.kubinyi.de
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Serendipity - Penicillin Molecular Conceptor
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Serendipity - Aspirin Molecular Conceptor
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Strategíes in Drug Design www.kubinyi.de
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3D Structures In Drug Research www.kubinyi.de
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Computational Approaches to Drug Discovery 4 Target identification 4 Lead discovery 4 Lead optimization 4 Ligand-based design 4 Receptor-based design (Docking) 4 Database screening (Virtual screening) 4 Supporting combinatorial chemistry
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Lead Structure Identification www.kubinyi.de
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Lead Structure Search www.kubinyi.de
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Lead Structures: Endogeneous Neurotransmitters www.kubinyi.de
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Lead Optimization www.kubinyi.de
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What is QSAR ?
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Basic Requirements in QSAR Studies
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QSAR www.kubinyi.de
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QSAR Parameters www.kubinyi.de
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QSAR Parameters
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QSAR Parameters -Lipophilicity
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QSAR Parameters www.kubinyi.de
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QSAR Parameters www.kubinyi.de
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QSAR Parameters www.kubinyi.de
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QSAR Parameters www.kubinyi.de
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QSAR Parameters www.kubinyi.de
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QSAR Parameters www.kubinyi.de
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A QSAR Success Story www.kubinyi.de
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A QSAR Success Story www.kubinyi.de pI 50 – concentration of test compound required to reduce the protein content of cell by 50%
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3D-QSAR - CoMFA www.kubinyi.de
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Molecular Superposition of D Receptor Ligands www.kubinyi.de
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The Future: Pharmagenomics and Personalized Medicine www.kubinyi.de
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3D-QSAR - CoMFA www.kubinyi.de
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3D-QSAR - CoMFA www.kubinyi.de
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Electrostatic and Van-der-Waals Interactions
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Drug Discovery – Ligand-based Design Comparative Molecular Field 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 Affinities www.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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Combinatorial Diversity in Nature www.kubinyi.de
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Classical vs. Combinational Chemistry ww.kubinyi.de
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Combinatorial Library ww.kubinyi.de
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Combinatorial Library ww.kubinyi.de
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Types and Features of Combinatorial Libraries ww.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 Screening ACD-SC: Database from Molecular Design Ltd. Agonists: Known active compounds Docking of ligands to the estrogen receptor (nuclear hormone receptor)
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Virtual Screening
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Lipinski‘s „Rule of Five“ Compounds are likely to have a good absorption and permeation in biological systems and are thus more likely to be successful drug candidates if 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 Medicine www.kubinyi.de
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Prediction Issues www.kubinyi.de
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