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Jürgen SühnelJürgen Sühneljsuehnel@imb-jena.dejsuehnel@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
Example of Drug Discovery Example of Drug Discovery
Example of Drug Discovery Example of Drug Discovery
Pacific yew tree(Eibe)
Example of Drug Discovery Example of Drug Discovery
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
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
Disciplines Involved in Drug DevelopmentDisciplines Involved in Drug Development
Molecular Conceptor
The Role of Molecular StructureThe Role of Molecular Structure
Molecular Conceptor
The Pharmacophore ConceptThe Pharmacophore Concept
Molecular Conceptor
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
Serendipity - AspirinSerendipity - Aspirin
Molecular Conceptor
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
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 ?
Basic Requirements in QSAR StudiesBasic Requirements in QSAR Studies
QSARQSAR
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QSAR ParametersQSAR Parameters
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QSAR ParametersQSAR Parameters
QSAR Parameters -LipophilicityQSAR Parameters -Lipophilicity
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%
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
Drug Discovery – Ligand-based DesignDrug Discovery – Ligand-based Design
ComparativeMolecularField Analysis
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
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
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Molecular Conceptor
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
Drug Discovery – Receptor-based Design (Structure-based Design)Drug Discovery – Receptor-based Design (Structure-based Design)
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)
Virtual ScreeningVirtual Screening
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“.
ADMEADME
The Future: Pharmagenomics and Personalized MedicineThe Future: Pharmagenomics and Personalized Medicine
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Prediction IssuesPrediction Issues
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