| Abstract: | Scoring functions are a critically important component of computer‐aided screening methods for the identification of lead compounds during early stages of drug discovery. Here, we present a new multigrid implementation of the footprint similarity (FPS) scoring function that was recently developed in our laboratory which has proven useful for identification of compounds which bind to a protein on a per‐residue basis in a way that resembles a known reference. The grid‐based FPS method is much faster than its Cartesian‐space counterpart, which makes it computationally tractable for on‐the‐fly docking, virtual screening, or de novo design. In this work, we establish that: (i) relatively few grids can be used to accurately approximate Cartesian space footprint similarity, (ii) the method yields improved success over the standard DOCK energy function for pose identification across a large test set of experimental co‐crystal structures, for crossdocking, and for database enrichment, and (iii) grid‐based FPS scoring can be used to tailor construction of new molecules to have specific properties, as demonstrated in a series of test cases targeting the viral protein HIVgp41. The method is available in the program DOCK6. © 2013 Wiley Periodicals, Inc. |
