Effect of substituent and π-stacking interaction on the metal chelation ability of 7-subestituted 2-oxyisoquinoline-1,3(2H,4H)-diones as an HIV integrase inhibitor: A DFT study

Abstract

Density functional theory (DFT) method was employed to a comprehensive and systematic study of the impact of substitution and π-stacking interaction on the metal chelation ability of 7-subestituted 2-oxyisoquinoline-1,3(2H,4H)-diones (OIQ−) that recently was found to be a potent HIV integrase inhibitor (INI). For this goal, first, the A||X−OIQ− complexes (where A is adenine, || indicates π-stacking interaction and X is CHO, CN, NO2, COOH, Cl, SH, SCH3, F, NH2, OH, OCH3, CH3 and H) were modeled and then interaction of these complexes with Mg2+ ions were investigated. The energy data showed the stability of the A||X−OIQ− complexes increase in the presence of all electron withdrawing substituents (EWSs) and some electron donating substituents (EDSs) (NH2, SCH3 and SH). Consequently, the electrostatic interactions caused by substituents alone are not sufficient to predict the trend of the stability of the A||X−OIQ− complexes but combination of substituent constants (σm, σi, and π) can predict binding energy (Ebind) of the complexes. Symmetry adapted perturbation theory energy decomposition (SAPT) calculation explained the importance of including an electrostatic term when predicting Ebind of the A||X−OIQ− complexes. Charge transfer (CT) from X−OIQ− to A in the A||X−OIQ− complexes and thereby decrease of the electrostatic potential (ESP) values around the oxygen atoms predicted the negative effect of the π-stacking interaction on the binding of stacked X−OIQ− to the Mg2+ ions which act as co-factor. This result was also confirmed by modeling the X−OIQ−⋯(Mg2+)2 and A||X−OIQ−⋯(Mg2+)2 complexes. In both the X−OIQ−⋯(Mg2+)2 and A||X−OIQ−⋯(Mg2+)2 complexes, unlike EWSs, EDSs effect on metal chelation is additive in comparison to unsubstituted one (X = H). The negative effect of π-stacking on the stacked X−OIQ− binding to the Mg2+ ions has also been studied by using the atoms in molecule (AIM) and natural population analysis (NPA) analyses which the results obtained agree with the energy data. The findings of this work can substantially shed light on new strategies for developing novel classes of HIV INIs with increased specificity and potency.