Divide-and-conquer-based quantum chemical study for interaction between HIV-1 reverse transcriptase and MK-4965 inhibitor

MK-4965, 3-{5-[(6-Amino-1H-pyrazolo[3,4-b]pyridine-3-yl)methoxy]-2- chlorophenoxy}-5-chloro-benzonitrile, is a novel non-nucleoside reverse transcriptase inhibitor (NNRTI) revealing high levels of potency against wild-type (WT) the human immunodeficiency virus type-1 (HIV-1) and some important mutants. The divide-and-conquer (DC) based Hartree-Fock (HF) and second-order Møller-Plesset perturbation theory (MP2) calculations were performed for the binding modes of MK-4965 in the reverse transcriptase (RT) of the WT HIV-1 and a mutant Y181C, 181 tyrosine mutated by cysteine. The binding pockets of MK-4965 consisting of 19 residues are selected for the study. Numerical assessments confirmed the efficiency and accuracy of the DC-MP2 method in comparison with the conventional MP2 one. Subsystem interaction energies obtained by the DC-MP2 calculations clarified the key parts of the binding between MK-4965 and HIV-1: hydrogen bonding with 102 lysine, which is apart from mutated 181 residue. The present information can give a helpful guide for the future inhibitor design.