LAUSR

A major challenge in computer‐aided drug design is the accurate estimation of ligand binding affinity. Here, a new approach that combines the adaptive steered molecular dynamics (ASMD) and partial atomic charges calculated by semi‐empirical quantum mechanics (SQMPC), namely ASMD‐SQMPC, is suggested to predict the ligand binding affinities, with 24 HIV‐1 protease inhibitors as testing examples. In the ASMD‐SQMPC, the relative binding free energy (ΔG) is reflected by the average maximum potential of mean force (max) between bound and unbound states. The correlation coefficient (R2) between the max and experimentally determined ΔG is 0.86, showing a significant improvement compared with the conventional ASMD (R2 = 0.52). Therefore, this study provides an efficient approach to predict the relative ΔG and reveals the significance of precise partial atomic charges in the theoretical simulations.