Fragment Based de novo Ligand Design: A Valuable Optimisation Tool in Fragment Based Lead Discovery

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SELECTBIO

Peter Johnson, Research Professor, University of Leeds

Abstract
De novo design software systems generate virtual molecules which satisfy certain constraints, typically the need to bind strongly to a target protein by virtue of electrostatic and shape complementarity. In the approach used by the SPROUT family of programs, fragment structures are selected from a library (or are tailor made by the user) and then docked to one or more 'hot spots' or target sites in a protein cavity to generate poses which are scored for estimated binding affinity. Larger structures are then built from the original docked fragments by a growing operation involving the successive addition of new fragments to an existing one (followed by redocking). The system can be used to generate complete new structures from scratch or to create modified versions of existing active molecules ie scaffold hopping and 'recore'. SPROUT has many applications in experimental FBDD including 1) selection of candidate fragments from a virtual library 2) guiding the protein structure based optimization of initial weak binding hits by a growing operation to either link two or more of the original docked fragments together or simply to make additional favourable contacts with the protein target. Examples of successful application in a number of medicinal chemistry projects will be discussed.