SynSPROUT: Virtual synthesis in protein cavities

ORGN 628

A. Peter Johnson, Krisztina Boda, Shane Weaver, and Vilmos Valko. School of Chemistry, University of Leeds, Leeds, LS2 9JT, 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. Although de novo design systems, like SPROUT, can generate many structurally diverse ligands which are predicted to bind tightly to a target protein, these hypothetical ligands have no practical significance unless they are also synthetically accessible. SYNSPROUT, a variant of SPROUT, incorporates synthetic constraints directly into the actual structure generation process, by using a library of readily available starting materials as well as fragment joining operations which mirror known chemical reactions. A variant, SPROUT LeadOpt, employs both retrosynthetic analysis and knowledge of available starting materials to suggest analogues of leads with improved predicted binding affinity. Experimental results relating to the application of these systems to the design and synthesis of specific enzyme inhibitors will be presented.