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Implementation and evaluation of a docking-rescoring method using molecular footprint comparisons.

ABSTRACT: A docking-rescoring method, based on per-residue van der Waals (VDW), electrostatic (ES), or hydrogen bond (HB) energies has been developed to aid discovery of ligands that have interaction signatures with a target (footprints) similar to that of a reference. Biologically useful references could include known drugs, inhibitors, substrates, transition states, or side-chains that mediate protein-protein interactions. Termed footprint similarity (FPS) score, the method, as implemented in the program DOCK, was validated and characterized using: (1) pose identification, (2) crossdocking, (3) enrichment, and (4) virtual screening. Improvements in pose identification (6–12%) were obtained using footprint-based (FPS(VDW+ES)) vs. standard DOCK (DCE(VDW+ES)) scoring as evaluated on three large datasets (680–775 systems) from the SB2010 database. Enhanced pose identification was also observed using FPS (45.4% or 70.9%) compared with DCE (17.8%) methods to rank challenging crossdocking ensembles from carbonic anhydrase. Enrichment tests, for three representative systems, revealed FPSVDW+ES scoring yields significant early fold enrichment in the top 10% of ranked databases. For EGFR, top FPS poses are nicely accommodated in the molecular envelope defined by the reference in comparison with DCE, which yields distinct molecular weight bias toward larger molecules. Results from a representative virtual screen of ca. 1 million compounds additionally illustrate how ligands with footprints similar to a known inhibitor can readily be identified from within large commercially available databases. By providing an alternative way to rank ligand poses in a simple yet directed manner we anticipate that FPS scoring will be a useful tool for docking and structure-based design.

SUBMITTER: Balius TE

PROVIDER: S-EPMC3181325 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Implementation and evaluation of a docking-rescoring method using molecular footprint comparisons.

Balius Trent E TE Mukherjee Sudipto S Rizzo Robert C RC

Journal of computational chemistry 20110503 10

A docking-rescoring method, based on per-residue van der Waals (VDW), electrostatic (ES), or hydrogen bond (HB) energies has been developed to aid discovery of ligands that have interaction signatures with a target (footprints) similar to that of a reference. Biologically useful references could include known drugs, inhibitors, substrates, transition states, or side-chains that mediate protein-protein interactions. Termed footprint similarity (FPS) score, the method, as implemented in the progra ...[more]

PMID: 21541962

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Project description:Molecular docking computationally screens thousands to millions of organic molecules against protein structures, looking for those with complementary fits. Many approximations are made, often resulting in low "hit rates." A strategy to overcome these approximations is to rescore top-ranked docked molecules using a better but slower method. One such is afforded by molecular mechanics-generalized Born surface area (MM-GBSA) techniques. These more physically realistic methods have improved models for solvation and electrostatic interactions and conformational change compared to most docking programs. To investigate MM-GBSA rescoring, we re-ranked docking hit lists in three small buried sites: a hydrophobic cavity that binds apolar ligands, a slightly polar cavity that binds aryl and hydrogen-bonding ligands, and an anionic cavity that binds cationic ligands. These sites are simple; consequently, incorrect predictions can be attributed to particular errors in the method, and many likely ligands may actually be tested. In retrospective calculations, MM-GBSA techniques with binding-site minimization better distinguished the known ligands for each cavity from the known decoys compared to the docking calculation alone. This encouraged us to test rescoring prospectively on molecules that ranked poorly by docking but that ranked well when rescored by MM-GBSA. A total of 33 molecules highly ranked by MM-GBSA for the three cavities were tested experimentally. Of these, 23 were observed to bind--these are docking false negatives rescued by rescoring. The 10 remaining molecules are true negatives by docking and false positives by MM-GBSA. X-ray crystal structures were determined for 21 of these 23 molecules. In many cases, the geometry prediction by MM-GBSA improved the initial docking pose and more closely resembled the crystallographic result; yet in several cases, the rescored geometry failed to capture large conformational changes in the protein. Intriguingly, rescoring not only rescued docking false positives, but also introduced several new false positives into the top-ranking molecules. We consider the origins of the successes and failures in MM-GBSA rescoring in these model cavity sites and the prospects for rescoring in biologically relevant targets.

Dataset Information

Implementation and evaluation of a docking-rescoring method using molecular footprint comparisons.

Publications

Implementation and evaluation of a docking-rescoring method using molecular footprint comparisons.

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