SynSPROUT and SPROUT-LeadOpt: De novo ligand design and optimization guided by virtual synthesis

COMP 37

A Peter Johnson, a.p.johnson@chemistry.leeds.ac.uk1, Vilmos Valko, vilmos.valko@keymodule.co.uk2, Aniko Valko1, Zsolt Zsoldos3, Krisztina Boda1, and Darryl Reid3. (1) School of Chemistry, University of Leeds, Leeds, LS2 9JT, United Kingdom, (2) Keymodule Ltd, Leeds, United Kingdom, (3) SimBioSys Inc, 135 Queen's Plate Dr, Suite 520, Toronto, ON M9W 6V1, Canada
The issue of synthetic accessibility has long plagued de novo ligand design. De novo design programs are in important tool in computational drug discovery. Programs such as SPROUT, can generate many structurally diverse ligands which are predicted to have high binding affinity, however, unless these structures are synthetically accessible, they have no practical use. Several methods have been implemented to deal with the problem of synthetic accessibility in SPROUT, including the CAESA package which estimates synthetic accessibility as a post de novo design filter. Two new variations of SPROUT will be discussed which use synthetic rules during the de novo design process to address the accessibility issue. SynSprout is a full de novo design tool that incorporates synthetic constraints directly in the actual structure generation process while SPROUT-LeadOpt employs both retrosynthetic analysis and knowledge of available starting materials to suggest analogues of leads with improved binding affinities. For more information see: http://www.simbiosys.ca/sprout/