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Computational tools for fragment based drug design

A. Peter Johnson, Zsolt Zsoldos, Aniko T. Valko, and Vilmos A. Valko
Presentation held at:
237th ACS National Meeting; CINF 33
March 2009, Salt Lake City, UT, USA

Although originally developed for complete de novo ligand design, the SPROUT software suite provides a set of tools ideally suited to the design of ligands incorporating one or more small fragments known through experimental methods (such as x-ray crystallography or nmr) to bind to specific regions of a target protein. In the case of a single fragment with known binding pose, SPROUT LeadOpt is able to apply a reaction knowledgebase and a set of available starting materials to carry out virtual reactions on the fragment to generate hypothetical ligands which are both readily synthesisable and also predicted to bind strongly to the target. Where two or more fragments bind in different regions, SPROUT is able to link them together, redocking to maintain the original poses, although also allowing some movement limited by user selected tolerances.

The technology used will be discussed together with examples illustrating its application.