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In molecular docking, it is challenging to develop a scoring function that is accurate to conduct high‐throughput screenings. Most scoring functions implemented in popular docking software packages were developed with many approximations for computational efficiency, which sacrifices the accuracy of prediction. With advanced technology and powerful computational hardware nowadays, it is feasible to use rigorous scoring functions, such as molecular mechanics/Poisson Boltzmann surface area (MM/PBSA) and molecular mechanics/generalized Born surface area (MM/GBSA) in molecular docking studies. Here, we systematically investigated the performance of MM/PBSA and MM/GBSA to identify the correct binding conformations and predict the binding free energies for 98 protein–ligand complexes. Comparison studies showed that MM/GBSA (69.4%) outperformed MM/PBSA (45.5%) and many popular …