Fragment-based methods for ligand optimization have great potential; however, time, expense and sensitivity considerations associated with NMR and x-ray crystallographic based methods limit their applicability.  As an alternative we have developed a computational approach, SILCS: Site Identification by Ligand Competitive Saturation, that uses explicit solvent all-atom molecular dynamics simulations to identify binding sites on protein surfaces for functional groups based on rigorous free energy criteria.  Information from the SILCS approach may then be combined with structural information on an inhibitor-protein complex to facilitate modification of the ligand to improve its binding affinity.  An overview of the SILCS approach and its application to inhibitor optimization in the context of blocking protein-protein interactions will be presented.

Site Identification by Ligand Competitive Saturation (SILCS): Mapping fragment binding sites including consideration of protein flexibility and fragment desolvation using an explicit solvent representation

245th National Meeting (2013)

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