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De novo design tools for the generation of synthetically accessible ligands

A. Peter Johnson, Krisztina Boda, Shane Weaver, Aniko T. Valko, and Vilmos A. Valko
School of Chemistry
University of Leeds
Leeds, LS2 9JT
United Kingdom
Presentation held at:
231st ACS National Meeting; CINF 29
March 2006, Atlanta, GA, USA

An efficient de novo design system can generate large numbers of hypothetical structures which have been tailored to bind to a specific receptor. An advantage of the de novo process is that many of these structures will have novel structural motifs. However, a possible disadvantage is that some of the structures might be relatively diffficult to synthesise. A number of different solutions to the synthetic accessibility problem have been developed for use with the SPROUT system for de novo design: a) CAESA - a separate system for assessment of synthetic feasibility b) SynSPROUT - a de novo system which incorporates synthetic feasibility into the de novo construction process c) Complexity analysis which matches the designed structures against substitution patterns of known drug like molecules d) SPROUT LeadOpt which optimises structures to improve binding affinity by application of known chemistry using available starting materials. The relative merits of these different approaches will be discussed.