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A role for chemoinformatics in structure-based de novo ligand design

A. Peter Johnson, Krisztina Boda, Tamas Lengyel, Shane Weaver, Aniko T. Vigh
School of Chemistry
University of Leeds
Leeds, LS2 9JT
United Kingdom
Presentation held at:
228th ACS National Meeting
August 2004, Philadelphia, PA

The SPROUT program for de novo ligand design benefits from extensive use made of chemical information extracted from a variety of databases and knowledge bases. Databases of x-ray structures such as CSD and the Brookhaven file provide support for the generation of conformations which should be of relatively low energy because they correspond to ones frequently found in these databases. Supplier catalogues, combined with retrosynthetic fragmentation of MDDR provide starting materials for the SynSPROUT variation in which structures are built up by virtual synthesis using common synthetic reactions stored in a reaction knowledge base. An alternative fragmentation of MDDR provides drug like entities which are flood docked to all possible target sites in a protein cavity. Analysis of the estimated binding affinity scores for all poses allows an informed choice of a subset of target sites for further structure generation.