LAUSR

Extensive usage of molecular docking for computer-aided drug discovery resulted in development of numerous programs with versatile scoring and posing algorithms. Selection of the docking program among these vast number of options is central to the outcome of drug discovery. To this end, comparative assessment studies of docking offer valuable insights into the selection of the optimal tool. Despite the availability of various docking assessment studies, the performance difference of docking programs has not been well addressed on metalloproteins which comprise a substantial portion of the human proteome and have been increasingly targeted for treatment of a wide variety of diseases. This study reports comparative assessment of 7 docking programs on a diverse metalloprotein set which was compiled for this study. The refined set of the PDBbind (2017) was screened to gather 710 complexes with metal ion(s) closely located to the ligands (<4 Å). The redundancy was eliminated by clustering and overall 213 complexes were compiled as the non-redundant metalloprotein subset of the PDBbind refined. The scoring, ranking and posing powers of 7 non-commercial docking programs, namely AutoDock4, AutoDock4Zn, AutoDock Vina, Quick Vina 2, LeDock, PLANTS and UCSF DOCK6 were comprehensively evaluated on this non-redundant set. Results indicated that PLANTS (80%) followed by LeDock (77%), QVina (76%) and Vina (73%) had the most accurate posing algorithms while AutoDock4 (48%) and DOCK6 (56%) were the least successful in posing. Contrary to their moderate-to-high level of posing success, none of the programs was successful in scoring or ranking of the binding affinities (r2 ≈ 0). Screening power was further evaluated by using active-decoy ligand sets for a large compilation of metalloprotein targets. PLANTS stood out among other programs to be able to enrich the active ligand for every target, underscoring its robustness for screening of metalloproteins inhibitors. This study provides useful information for drug discovery studies targeting metalloproteins.