Modulation of the induced π-stacking interactions between the active site cytosine moiety of HIV-integrase and inhibitors containing substituted-methylbenzene: Physical nature of the positional and substituent effects

• Published in: Journal of molecular structure 2020-01, Vol.1199, p.126950, Article 126950
• Main Authors: Farrokhzadeh, Abdolkarim, Akher, Farideh Badichi, Honarparvar, Bahareh, Van Heerden, Fanie R.
• Format: Article
• Language: English
• Subjects: Constant substituent; Cytosine; ESP; HIV-Integrase; SAPT; π-Stacking interaction
• ISSN: 0022-2860; 1872-8014
• DOI: 10.1016/j.molstruc.2019.126950

Although the π-stacking interaction between the substituted aromatic ring of small molecule inhibitors and the cytosine nucleobase present at the active site of HIV integrase (IN) are abundantly seen, no current study systematically covers differing positional substituents. Herewith, we report a comprehensive and systematic study aimed at unraveling the nature of substituent effects on model C||X-MB-Y (|| denotes π-stacking interaction, X is CHO, CN, NO2, COOH, Cl, SH, SCH3, F, NH2, OH, OCH3, CH3 and H; MB denotes methylbenzene and Y typifies diverse substituent positioning which includes m1, m2, o1, o2 and p) based on findings from the methodical incorporation of B3LYP-D3/6-311++G(d,p) binding energy (Ebind) as well as symmetry-adopted perturbation theory (SAPT) results. Energy data indicated that stability of the C||X-MB-Y complexes increased in the presence of both the electron-withdrawing substituents (EWSs) and electron-donating substituents (EDSs) relative to the unsubstituted ones (X = H). Moreso, the lack of a good correlation between Ebind and σmeta confirmed that the mechanism by which the various substituents facilitated the stability of each complex is not only by electrostatic interactions. In agreement with this finding, it was observed in this study that the combination of different substituent constant terms for all positions gave excellent correlations with Ebind. In addition, the results indicated that the strength of π-stacking interactions depends on the corresponding orientations of interacting rings. Also, it was observed that the most stable complexes for EWSs and EDSs corresponded to positions o1 and o2, respectively. Estimations of SAPT revealed the importance of the electrostatic term (Eele) in the prediction of Ebind for each position, except at position m2, where all energy components played important roles in the stability of the complexes. Also, comparative studies of the different positions indicated that the stability of the complexes decreases by a decreasing Eele. [Display omitted] •The mechanisms by which the various substituents facilitated the stability of each complexes is not only by electrostatic interactions.•The strength of π-stacking interactions also depends on the corresponding orientations of interacting rings.•Estimations of SAPT revealed the importance of electrostatic term (Eele) in the prediction of Ebind for each position, except at position m2.