COMP 246 |
| Combinatorial Chemistry is an efficient technique to provide tailor-made compound libraries preferably leading to new lead structures modulating the function of a target protein. Herein we present a computational combinatorial method where building blocks are derived from a search of generated target protein subpockets. We selected the serine protease thrombin as a well established model case. Subpockets are compared with all stored binding pockets in CAVBASE.All fragments which bind to similar subpockets are extracted. Subsequently, a substructure search is performed giving rise to a subset of putative building blocks with suitable functional groups for the later synthesis. The obtained building blocks are docked combinatorially using FlexXC. Through re-scoring with scoring functions developed in our group, a subset of the most promising library members is generated.Subsequent synthesis of single members of the generated library followed by experimental affinity determination validated our knowledge-based strategy of building block generation. |
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Poster Session
6:00 PM-8:00 PM, Tuesday, 12 September 2006 Moscone Center -- Hall D, Poster
Sci-Mix
Division of Computers in Chemistry |