AbstractMK‐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. © 2012 Wiley Periodicals, Inc.