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3D Structures of Biological Macromolecules Part 3: Drug Research and Design Jürgen Sühnel [email protected] Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena Centre for Bioinformatics Jena / Germany Supplementary Material: www.fli-leibniz.de/www_bioc/3D/ Example of Drug Discovery Example of Drug Discovery Example of Drug Discovery Pacific yew tree (Eibe) Drug Research is the Search for a Needle in a Haystack. www.kubinyi.de Development of Drug Research www.kubinyi.de Drug Timeline www.kubinyi.de Drug Timeline www.kubinyi.de Costs in Drug Research Cost for discovering and developing a new drug: several € 100 million up to € 1000 million (average € 802 M) Time to market: 10 – 15 years Global Company Sales 2006 Top Ethical Drugs by Sales in 2006 http://www.p-d-r.com/ranking/Top_100_Ethical_Drugs_by_Sales.pdf New Products Marketed for the First Time http://www.p-d-r.com/ranking/Prous_TYND_2005.pdf Disciplines Involved in Drug Development Molecular Conceptor The Role of Molecular Structure Molecular Conceptor The Pharmacophore Concept Molecular Conceptor Mechanisms of Drug Action – Definitions I www.kubinyi.de Mechanisms of Drug Action – Definitions II www.kubinyi.de Serendipity - Penicillin Molecular Conceptor Serendipity - Penicillin Serendipity - Aspirin Serendipity - Aspirin Molecular Conceptor Strategies in Drug Design www.kubinyi.de Computational Approaches to Drug Research Target identification Lead discovery Lead optimization Ligand-based design Receptor-based design (Docking) Database screening (Virtual screening) Supporting combinatorial chemistry 3D Structures in Drug Design www.kubinyi.de Lead Structure Identification www.kubinyi.de Lead Structure Search Pipeline www.kubinyi.de Lead Structures: Endogenous Neurotransmitters www.kubinyi.de Lead Structures: Endogenous Neurotransmitters Neurotransmitters are chemicals that are used to relay, amplify and modulate electrical signals between a neuron and another cell. Acetylcholine: Noradrenaline: Dopamine: Serotonin: GABA: voluntary movement of the muscles wakefulness or arousal voluntary movement and emotional arousal sleep and temperature regulation (gamma aminobutryic acid) - motor behaviour www.kubinyi.de Lead Optimization www.kubinyi.de Ligand-based Design: What is QSAR ? Ligand-based Design: Basic Requirements for QSAR Studies Ligand-based Design: QSAR Hansch analysis is the investigation of the quantitative relationship between the biological activity of a series of compounds and their physicochemical substituent or global parameters representing hydrophobic, electronic, steric and other effects using multiple regression correlation methodology. www.kubinyi.de Ligand-based Design: QSAR Parameters www.kubinyi.de Ligand-based Design: QSAR Parameters Ligand-based Design: QSAR Parameters - Lipophilicity Ligand-based Design: QSAR Parameters www.kubinyi.de Ligand-based Design: QSAR Parameters www.kubinyi.de Ligand-based Design: QSAR Parameters www.kubinyi.de Ligand-based Design: QSAR Parameters www.kubinyi.de Ligand-based Design: QSAR Parameters www.kubinyi.de Ligand-based Design: QSAR Parameters www.kubinyi.de Ligand-based Design: A QSAR Success Story www.kubinyi.de Ligand-based Design: A QSAR Success Story pI50 – concentration of test compound required to reduce the protein content of cell by 50% www.kubinyi.de Ligand-based Design: 3D-QSAR CoMFA www.kubinyi.de Molecular Superposition of D Receptor Ligands www.kubinyi.de Ligand-based Design: 3D-QSAR CoMFA www.kubinyi.de Ligand-based Design: 3D-QSAR CoMFA www.kubinyi.de Electrostatic and Van-der-Waals Interactions Ligand-based Design: 3D-QSAR CoMFA Comparative Molecular Field Analysis Receptor-based Design (Structure-based Design) Molecular Conceptor Receptor-based Design (Structure-based Design) Molecular Conceptor Receptor-based Design: Docking Molecular Conceptor Receptor-based Design: Docking Molecular Conceptor Receptor-based Design: Docking Molecular Conceptor Hydrophobic Amino Acids Molecular Conceptor Receptor-based Design: Docking Molecular Conceptor H-Bond Properties of Amino Acids Molecular Conceptor Receptor-based Design: H-bond Effect IC50 Drug concentration required for 50% inhibition of a biological effect Molecular Conceptor Receptor-based Design: H-bond Effect www.kubinyi.de Charge Properties of Amino Acids Molecular Conceptor Receptor-based Design: Salt Bridge 116. Molecular Conceptor Receptor-based Design: Docking Molecular Conceptor Receptor-based Design: SAR (Pharmacophore Features) Molecular Conceptor Receptor-based Design: DNA Receptor Molecular Conceptor Receptor-based Design: DNA Intercalating Agents Molecular Conceptor Receptor-based Design: DNA Intercalating Agents Molecular Conceptor Receptor-based Design: AIDS Drugs Receptor-based Design: AIDS Drugs Combinatorial Diversity in Nature www.kubinyi.de Classical vs. Combinatorial Chemistry ww.kubinyi.de Combinatorial Library ww.kubinyi.de Combinatorial Library ww.kubinyi.de Types and Features of Combinatorial Libraries ww.kubinyi.de Receptor-based Design: Virtual Screening 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 Docking of the 1.1 million data set 30 s (SGI R10000 processor) 6 days (64-processor SGI ORIGIN) ACD-SC: Database from Molecular Design Ltd. Agonists: Known active compounds Docking of ligands to the estrogen receptor (nuclear hormone receptor) Receptor-based Design: Virtual Screening 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“. Druggable compounds ADME ADME The Future: Pharmacogenomics and Personalized Medicine www.kubinyi.de Prediction Issues www.kubinyi.de