Post on 24-Sep-2015
description
Jrgen Shneljsuehnel@imb-jena.deInstitute 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
Example of Drug Discovery
Drug discovery Example of Drug Discovery
Pacific yew tree(Eibe)Example of Drug Discovery
Development of Drug Researchwww.kubinyi.de
Drug Timelinewww.kubinyi.de
Drug Timelinewww.kubinyi.de
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
Costs in Drug Researchww.kubinyi.de
Pharma Sales and Eearnings in 1999-2002ww.kubinyi.de
The Worlds Top-Selling Drugs in 2004
Disciplines Involved in Drug DevelopmentMolecular Conceptor
The Role of Molecular StructureMolecular Conceptor
The Pharmacophore ConceptMolecular Conceptor
Mechanisms of Drug Action Definitions Iwww.kubinyi.de
Mechanisms of Drug Action Definitions IIwww.kubinyi.de
Serendipity - PenicillinMolecular Conceptor
Serendipity - AspirinMolecular Conceptor
Strateges in Drug Designwww.kubinyi.de
3D Structures In Drug Researchwww.kubinyi.de
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
Lead Structure Identificationwww.kubinyi.de
Lead Structure Searchwww.kubinyi.de
Lead Structures: Endogeneous Neurotransmitterswww.kubinyi.de
Lead Optimizationwww.kubinyi.de
What is QSAR ?
Basic Requirements in QSAR Studies
QSARwww.kubinyi.de
QSAR Parameterswww.kubinyi.de
QSAR Parameters
QSAR Parameters -Lipophilicity
QSAR Parameterswww.kubinyi.de
QSAR Parameterswww.kubinyi.de
QSAR Parameterswww.kubinyi.de
QSAR Parameterswww.kubinyi.de
QSAR Parameterswww.kubinyi.de
QSAR Parameterswww.kubinyi.de
A QSAR Success Storywww.kubinyi.de
A QSAR Success Storywww.kubinyi.depI50 concentration of test compound required to reduce the protein content of cell by 50%
3D-QSAR - CoMFAwww.kubinyi.de
Molecular Superposition of D Receptor Ligandswww.kubinyi.de
The Future: Pharmagenomics and Personalized Medicinewww.kubinyi.de
3D-QSAR - CoMFAwww.kubinyi.de
3D-QSAR - CoMFAwww.kubinyi.de
Electrostatic and Van-der-Waals Interactions
Drug Discovery Ligand-based DesignComparativeMolecularField Analysis
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Hydrogen Bonds and Ligand Affinitieswww.kubinyi.de
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
Drug Discovery Receptor-based Design (Structure-based Design)Molecular Conceptor
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)
Combinatorial Diversity in Naturewww.kubinyi.de
Classical vs. Combinational Chemistryww.kubinyi.de
Combinatorial Libraryww.kubinyi.de
Combinatorial Libraryww.kubinyi.de
Types and Features of Combinatorial Librariesww.kubinyi.de
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)
Virtual Screening
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.
ADME
The Future: Pharmagenomics and Personalized Medicinewww.kubinyi.de
Prediction Issueswww.kubinyi.de