Consensus scoring evaluated using the GPCR-Bench dataset: Reconsidering the role of MM/GBSA.

The recent availability of large numbers of GPCR crystal structures has provided an unprecedented opportunity to evaluate their performance in virtual screening protocols using established benchmarking datasets. In this study, we evaluated the ability of MM/GBSA in consensus scoring-based virtual screening enrichment together with nine classical scoring functions, using the GPCR-Bench dataset consisting of 24 GPCR crystal structures and 254,646 actives and decoys. While the performance of consensus scoring was modest overall, combinations which included MM/GBSA performed relatively well compared to combinations of classical scoring functions. Combinations of MM/GBSA and good-performing scoring functions provided the highest proportion of improvements, with improvements observed in 32% and 19% of all combinations across all targets at the EF and EF levels respectively. Combinations of MM/GBSA and poor-performing scoring functions still outperformed classical scoring functions, with improvements observed in 26% and 17% of all combinations at the EF and EF levels. In comparison, only 14-22% and 6-11% of combinations of classical scoring functions produced improvements at EF and EF respectively. Efforts to improve performance by increasing the number of scoring functions in consensus scoring to three were mostly ineffective. We also observed that consensus scoring performed better for individual scoring functions possessing initially low enrichment factors, potentially implying their benefits are more relevant in such scenarios. Overall, this study demonstrated the first implementation of MM/GBSA in consensus scoring using the GPCR-Bench dataset and could provide a valuable benchmark of the performance of MM/GBSA in comparison to classical scoring functions in consensus scoring for GPCRs.