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Fragment evolution using SPROUT-HitOpt

Vilmos A. Valko, A. Peter Johnson
Poster presented at:
Fragment-based Lead Discovery Conference 2009
September 2009, York, United Kingdom

The SPROUT family of molecular structure design software, consisting of SPROUT, SynSPROUT and SPROUT-HitOpt, provide three different approaches for designing ligands that fit the steric and chemical constraints of a protein receptor. SPROUT performs an exhaustive exploration of the search space, joining predefined fragments together to suggest novel ligands. SynSPROUT generates skeletons from fragments by using joins which correspond exactly to chemical reactions, with the monomers being chosen from a library of readily available starting materials. The starting point for SPROUT-HitOpt is an existing ligand which is typically a structure known to bind to a receptor site. Using virtual synthetic chemistry this structure is optimised, either by core extension (by reaction at existing or modified functional groups) or monomer replacement (existing parts of the molecule replaced by structurally related units).

SynSPROUT and SPROUT-HitOpt are useful tools for FBDD, the former provides synthetic chemistry based linking technology, and the latter provides a mechanism for fragment evolution. The poster will illustrate the application of these techniques to FBDD with examples which exemplify the scope and limitations of the approach.