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Fifth European Workshop in Drug Design May 29 - June 05, 2005 Case studies
------------------------------------------------------------------- DISCLAIMER To encourage open communication, each member of the Fifth European Workshop in Drug Design agrees that any information presented at the Workshop or used in one of the case study sessions is private information from individuals (organizations) making the contribution and is presented or used with the restriction that such information is not for public use. -------------------------------------------------------------------
Design of potential subtype-specific CDK-Inhibitors Thierry Langer, University of Innsbruck, Austria Wolfgang Sippl, University of Halle, Germany
In this workgroup we will show how computer aided molecular modelling techniques may be applied to the design of subtype-specific cyclin-dependent kinase (CDK) inhibitors. CDKs play a key role in regulating the cell cycle machinery. An increasing body of evidence has shown a link between tumor development and CDK-related malfunctions. This evidence has led to an intense search for small molecule inhibitors of the CDK family as an approach to cancer chemotherapy. Starting from the X-ray structure of CDKs (2 and 6), a structure-based approach will be used for generating pharmacophore based filter templates that can be employed for filtering large virtual compound libraries. Hits obtained will be docked into the binding site and different scoring functions will be studied in order to rank the compounds according to their expected binding affinity. For CDKs without a solved x-ray structure subtypes, ligand-based techniques will be used together with homology modelling in order to find potential inhibitors. Virtual libraries will be built according to the features determined to be crucial for binding and explored for containing potential inhibitors. A variety of software packages will be applied, covering the cutting edge technologies available at present time.
Ref.: 1. Designing inhibitors of cyclin-dependent kinases, Hardcastle IR, Golding BT, Griffin RJ., Annu Rev Pharmacol Toxicol. 2002, 42, 325-48. 2. Pharmacological inhibitors of cyclin-dependent kinases. Knockaert M, Greengard P, Meijer L., Trends Pharmacol Sci. 2002, 23, 417-25.
GRID-based Molecular Interaction Field in Cheminformatics and Drug Design. Gabriele Cruciani, Università di Perugia - Italy Contents: Basic principles of GRID force fiels 4-points pharmacophoric search from GRID Docking with Molecular Interaction Fields Progress in ADME fields using GRID-MIF Metabolism prediction using GRID-MIF
Homology modelling and docking on a protein target to be defined Anna Tramontano, University “La Sapienza”, Roma - Italy Andrea Tafi, University of Siena - Italy Hanoch Senderowitz, Predix Pharmaceutical Ltd - Israel
This case study deals with protein modelling and docking. Possible projects, which are being defined, are: We will dock a transition state analogue of a reaction into the antigen binding site of a modelled catalytic antibody. The steps required are 1. Modelling of the antibody 2. Docking of the transition state analogue 3. Rational modifying the binding site to improve catalytic efficiency Alternatively (or in addition if there is enough time): The antigen binding site of an antibody raised against a yeast protein will be redesigned for binding the human protein counterpart. In this case, the steps would be: 1. Modelling of the human protein using its yeast homologue as template 2. Redesign of the antigen binding site to provide the new interface. Some references about the topics that will be treated in the case study/ies will be posted here soon.
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