Benchmarking the performance of MM/PBSA in virtual screening enrichment using the GPCR-Bench dataset.
Recent breakthroughs in G protein-coupled receptor (GPCR) crystallography and the subsequent increase in number of solved GPCR structures has allowed for the unprecedented opportunity to utilize their experimental structures for structure-based drug discovery applications. As virtual screening represents one of the primary computational methods used for the discovery of novel leads, the GPCR-Bench dataset was created to facilitate comparison among various virtual screening protocols. In this study, we have benchmarked the performance of Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) in improving virtual screening enrichment in comparison to docking with Glide, using the entire GPCR-Bench dataset of 24 GPCR targets and 254,646 actives and decoys. Reranking the top 10% of the docked dataset using MM/PBSA resulted in improvements for six targets at EF1% and nine targets at EF5%, with the gains in enrichment being more pronounced at the EF1% level. We additionally assessed the utility of rescoring the top ten poses from docking and the ability of short MD simulations to refine the binding poses prior to MM/PBSA calculations. There was no clear trend of the benefit observed in both cases, suggesting that utilizing a single energy minimized structure for MM/PBSA calculations may be the most computationally efficient approach in virtual screening. Overall, the performance of MM/PBSA rescoring in improving virtual screening enrichment obtained from docking of the GPCR-Bench dataset was found to be relatively modest and target-specific, highlighting the need for validation of MM/PBSA-based protocols prior to prospective use.
['Yau|Mei Qian|MQ|', 'Emtage|Abigail L|AL|', 'Loo|Jason S E|JSE|0000-0001-6976-3282']
D019985:Benchmarking D001665:Binding Sites D062126:Databases, Chemical D004353:Drug Evaluation, Preclinical D006801:Humans D062105:Molecular Docking Simulation D016012:Poisson Distribution D011485:Protein Binding D011487:Protein Conformation D043562:Receptors, G-Protein-Coupled D013816:Thermodynamics
MM/PBSA Virtual screening GPCR