title: Grid-based molecular footprint comparison method for docking and de novo design: application to HIVgp41.
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.
authors: Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, New York 11794, USA.
authors: Trent E
authors: TE
authors: Balius
authors: Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, New York 11794, USA.
authors: William J
authors: WJ
authors: Allen
authors: Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, New York 11794, USA.
authors: Sudipto
authors: S
authors: Mukherjee
authors: Department of Applied Mathematics & Statistics, Stony Brook University, Stony Brook, New York 11794, USA.|Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, New York 11794, USA.|Laufer Center for Physical & Quantitative Biology, Stony Brook University, Stony Brook, New York 11794, USA.
authors: Robert C
authors: RC
authors: Rizzo
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D015195:Drug Design; D006678:HIV / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D006801:Humans; D062105:Molecular Docking Simulation; D011485:Protein Binding
chemical_list: D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41