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Transcript of Jürgen Sühnel [email protected] Institute of Molecular Biotechnology, Jena Centre for...
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Jürgen SühnelJürgen Sü[email protected]@imb-jena.de
Institute of Molecular Biotechnology, Jena Centre for BioinformaticsInstitute of Molecular Biotechnology, Jena Centre for BioinformaticsJena / GermanyJena / Germany
Supplementary Material: http://www.imb-jena.de/www_bioc/3D/
3D Structures of Biological Macromolecules3D Structures of Biological MacromoleculesPart 3Part 3
Drug Research and Design Drug Research and Design
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Example of Drug Discovery Example of Drug Discovery
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Example of Drug Discovery Example of Drug Discovery
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Pacific yew tree(Eibe)
Example of Drug Discovery Example of Drug Discovery
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Development of Drug ResearchDevelopment of Drug Research
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Drug TimelineDrug Timeline
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Drug TimelineDrug Timeline
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Drug DiscoveryDrug 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 ResearchCosts in Drug Research
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Pharma Sales and Eearnings in 1999-2002Pharma Sales and Eearnings in 1999-2002
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The World´s Top-Selling Drugs in 2004The World´s Top-Selling Drugs in 2004
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Disciplines Involved in Drug DevelopmentDisciplines Involved in Drug Development
Molecular Conceptor
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The Role of Molecular StructureThe Role of Molecular Structure
Molecular Conceptor
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The Pharmacophore ConceptThe Pharmacophore Concept
Molecular Conceptor
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Mechanisms of Drug Action – Definitions IMechanisms of Drug Action – Definitions I
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Mechanisms of Drug Action – Definitions IIMechanisms of Drug Action – Definitions II
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Serendipity - PenicillinSerendipity - Penicillin
Molecular Conceptor
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Serendipity - AspirinSerendipity - Aspirin
Molecular Conceptor
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Strategíes in Drug DesignStrategíes in Drug Design
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3D Structures In Drug Research3D Structures In Drug Research
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Computational Approaches to Drug DiscoveryComputational 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 IdentificationLead Structure Identification
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Lead Structure SearchLead Structure Search
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Lead Structures: Endogeneous NeurotransmittersLead Structures: Endogeneous Neurotransmitters
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Lead OptimizationLead Optimization
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What is QSAR ?What is QSAR ?
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Basic Requirements in QSAR StudiesBasic Requirements in QSAR Studies
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QSARQSAR
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QSAR ParametersQSAR Parameters
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QSAR ParametersQSAR Parameters
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QSAR Parameters -LipophilicityQSAR Parameters -Lipophilicity
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QSAR ParametersQSAR Parameters
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QSAR ParametersQSAR Parameters
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QSAR ParametersQSAR Parameters
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QSAR ParametersQSAR Parameters
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QSAR ParametersQSAR Parameters
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QSAR ParametersQSAR Parameters
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A QSAR Success StoryA QSAR Success Story
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A QSAR Success StoryA QSAR Success Story
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pI50 – concentration of test compound required to reduce the protein content of cell by 50%
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3D-QSAR - CoMFA3D-QSAR - CoMFA
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Molecular Superposition of D Receptor LigandsMolecular Superposition of D Receptor Ligands
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The Future: Pharmagenomics and Personalized MedicineThe Future: Pharmagenomics and Personalized Medicine
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3D-QSAR - CoMFA3D-QSAR - CoMFA
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3D-QSAR - CoMFA3D-QSAR - CoMFA
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Electrostatic and Van-der-Waals InteractionsElectrostatic and Van-der-Waals Interactions
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Drug Discovery – Ligand-based DesignDrug Discovery – Ligand-based Design
ComparativeMolecularField Analysis
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Hydrogen Bonds and Ligand AffinitiesHydrogen Bonds and Ligand Affinities
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
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Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
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Combinatorial Diversity in NatureCombinatorial Diversity in Nature
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Classical vs. Combinational ChemistryClassical vs. Combinational Chemistry
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Combinatorial LibraryCombinatorial Library
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Combinatorial LibraryCombinatorial Library
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Types and Features of Combinatorial LibrariesTypes and Features of Combinatorial Libraries
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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 set 6 days
(64-processor SGI ORIGIN)
Virtual ScreeningVirtual Screening
ACD-SC: Database from Molecular Design Ltd.Agonists: Known active compoundsDocking of ligands to the estrogen receptor (nuclear hormone receptor)
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Virtual ScreeningVirtual Screening
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Lipinski‘s „Rule of Five“Lipinski‘s „Rule of Five“
Compounds 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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ADMEADME
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The Future: Pharmagenomics and Personalized MedicineThe Future: Pharmagenomics and Personalized Medicine
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Prediction IssuesPrediction Issues
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