Compromise in Docking Power of Liganded Crystal Structures of Mpro SARS-CoV-2 Surpasses 90% Success Rate.

Abstract

Herein, we present the capacity of three different molecular docking programs (AutoDock, AutoDock Vina, and PLANTS) to identify and reproduce the binding modes of ligands present in 247 covalent and 169 noncovalent complex crystal structures of the severe acute respiratory syndrome coronavirus 2 main protease (Mpro). The compromise in docking power is evaluated with respect to their ability to generate poses similar to the crystal structure binding mode (heavy atoms' root-mean-square deviation < 2 Å) and their ability to recognize the native binding mode with an included compensation for the scoring function error. Noncovalently bound inhibitors are best modeled by AutoDock Vina (90.6% success rate in the active site), while the most relevant results for covalently bound inhibitors are produced by PLANTS (93.0%). AutoDock shows acceptable performance for both types of ligands, 81.1 and 76.4% for noncovalent and covalent complexes, respectively. All three programs manifest worse performance when reproducing surface-bound ligands. Comparison with other works illustrates the importance of crystal structure processing (12% of noncovalent and 26% of covalent ligands had to be manually corrected), proper sampling protocol settings, and inclusion of root-mean-square deviation (RMSD)/scoring function error compensations in crystal structure pose identification. Results are analyzed with respect to a clustering scheme of the noncovalently bound ligands and the chemical reaction type of the covalent ligand bound to the Cys145 residue. A comparison of screening power based on the docking scores of noncovalent ligands from the crystal structures with a "Directory of Useful Decoys, Enhanced" set of known decoys (6562 compounds) and ZINC15 in vivo subset (60,394 compounds) is provided. Ligand and protein input files are provided for future benchmarking purposes.