Abstract
Comparison of ligand poses generated by protein–ligand docking programs has often been carried out with the assumption of direct atomic correspondence between ligand structures. However, this correspondence is not necessarily chemically relevant for symmetric molecules and can lead to an artificial inflation of ligand pose distance metrics, particularly those that depend on receptor superposition (rather than ligand superposition), such as docking root mean square deviation (RMSD). Several of the commonly-used RMSD calculation algorithms that correct for molecular symmetry do not take into account the bonding structure of molecules and can therefore result in non-physical atomic mapping. Here, we present DockRMSD, a docking pose distance calculator that converts the symmetry correction to a graph isomorphism searching problem, in which the optimal atomic mapping and RMSD calculation are performed by an exhaustive and fast matching search of all isomorphisms of the ligand structure graph. We show through evaluation of docking poses generated by AutoDock Vina on the CSAR Hi-Q set that DockRMSD is capable of deterministically identifying the minimum symmetry-corrected RMSD and is able to do so without significant loss of computational efficiency compared to other methods. The open-source DockRMSD program can be conveniently integrated with various docking pipelines to assist with accurate atomic mapping and RMSD calculations, which can therefore help improve docking performance, especially for ligand molecules with complicated structural symmetry.
Highlights
Computer-aided drug design, in particular protein– ligand docking, has brought about the discovery of many biologically active drugs [1, 2]
Docking conformation dataset and generation To evaluate DockRMSD’s symmetry correction and the reliability of the greedy search heuristic, we generated docking conformations based on the CSAR Hi-Q protein-ligand dataset [21]
Docking root mean square deviation (RMSD) was calculated between all 10 possible pairwise combinations of the top five poses generated from a single re-docking experiment, leading to a total of 3430 RMSD calculations (10 per protein–ligand pair, 343 protein–ligand pairs in total)
Summary
Computer-aided drug design, in particular protein– ligand docking, has brought about the discovery of many biologically active drugs [1, 2]. Since the ability of these programs to accurately assess binding affinity is dependent on their ability to find the optimal conformation of the ligand in the protein binding pocket, docking programs are often benchmarked by their ability to reproduce the native binding pose of a ligand from a protein–ligand complex crystal structure. Docking RMSD can be most naïvely calculated with the assumption of direct atomic correspondence, or in other words, the assumption that the atomic labels between ligand structures in the given structure files are ordered and should remain static in the docking process. This assumption holds for asymmetric molecules like
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