This presentation will emphasize development and validation of a new DOCK scoring function, termed footprint similarity (FPS) score, which is being applied to aid several ongoing lead discovery and refinement projects in our laboratory targeting HIVgp41, FABP, and botulinum neurotoxin.  The method utilizes a reference compound, bound to the target protein, to identify small organic molecules that make similar footprint patterns in terms of per-residue van der Waals and electrostatic interactions.  References can include a known inhibitor, substrate, cofactor, or, as in the case for HIVgp41, a select group of side-chains along a protein-protein interface.  FPS scoring can be used as a rescoring tool (Cartesian space) or employed to influence on-the-fly flexible ligand sampling (multi-grid space).  Results using the method to guide virtual screens, as well as preliminary studies using an early-stage de novo design version of DOCK that employs FPS scoring to guide lead refinement and ligand growth, will be presented.

Strategies for lead discovery using footprint similarity scoring

247th National Meeting (2014)

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