Molecular dynamics simulation-based evaluation of the binding free energies of computationally designed drug candidates: importance of the dynamical effects

The computational structure-based drug design (SBDD) mainly aims at generating or discovering new chemical compounds with sufficiently large binding free energy. In any de novo drug design methods and virtual screening methods, drug candidates are selected by approximately evaluating the binding free energy (or the binding affinity). This approximate binding free energy, usually called "empirical score," is critical to the success of the SBDD. The purpose of this work is to yield physical insight into the approximate evaluation method in comparison with an exact molecular dynamics (MD) simulation-based method (named MP-CAFEE), which can predict binding free energies accurately. We calculate the binding free energies for 58 selected drug candidates with MP-CAFEE. Here, the compounds are generated by OPMF, a novel fragment-based de novo drug design method, and the ligand-protein interaction energy is used as an empirical score. The results show that the correlation between the binding free energy and the interaction energy is not strong enough to clearly distinguish compounds with nM-affinity from those with µM-affinity. This implies that it is necessary to take into account the natural protein motion with explicitly surrounded by water molecules to improve the efficiency of the drug candidate selection procedure.