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SPROUT LeadOpt: protein structure based lead optimisation

A. Peter Johnson, Krisztina Boda, Philip Bone, Shane Weaver, Aniko T. Valko, and Vilmos A. Valko
School of Chemistry
University of Leeds
Leeds, LS2 9JT
United Kingdom
Presentation held at:
4th Sheffield Conference on Chemoinformatics
June 2007, Sheffield, United Kingdom

De novo design is an important computational tool in protein structure based drug design in which structures are built up by linking together small 3D fragments within the binding cavity of the protein target. True de novo design systems, like SPROUT, can generate many structurally diverse ligands which are predicted to bind tightly to a target protein. Synthetic accessibility of these hypothetical ligands is an important factor in choosing between alternative hits and a number of different methods have been developed to address this problem. Lead optimisation is a different, though no less important problem in structure based drug design, and a variant of SPROUT has been developed to address this problem. SPROUT LeadOpt, employs both retrosynthetic analysis and knowledge of available starting materials to suggest analogues of leads with improved predicted binding affinity. It comprises two modules - Core Extension and Monomer Replacement to provide alternative modes of lead optimisation. The way in which these systems operate will be presented, along with experimental results relating to the application of these systems to the design and synthesis of specific enzyme inhibitors.