Molecular modelling studies on 2-amino 6-aryl-sulphonylbenzonitriles as non-nucleoside reverse transcriptase inhibitors of HIV-1: A QSPR approach

Abstract

Lipophilicity or hydrophobicity is a crucial physico-chemical property of an oral drug compound. In the present study, we have analysed the structural parameters responsible for enhancing the lipophilicity expressed in terms of Octanol-Water partition coefficient, log P, of 2-amino-6-arylsulfonylbenzonitrile (AASBN) derivatives used as NNRTIs in AIDS therapy. Connectivity based Randic (χ) and Balaban (J) and atomistic Kier-Hall electrotopological state (E-state) indices have been used to develop Quantitative Structure-Property Relationship (QSPR) and to predict the effect of substitution on the log P. Model has been developed using multiple linear regression analysis (MLR) for the training set (67 compounds) and the model was tested on a test set (7 compounds). Significant results were obtained for the training set (R 2 = 0⋅948, R 2 adj = 0⋅939, SE = 0⋅177, F-ratio = 101⋅22). The results of the test set too implicated a good fit (R 2 = 0⋅941, R 2 adj = 0⋅929, SE = 0⋅157, F-ratio = 80⋅05). Among the two connectivity based topological indices; Randic (χ) index showed better predictive ability than the Balaban (J) index. Kier-Hall E-state indices indicated that among the functional groups, methyl, bromo, chloro groups on ring A, with their positive coefficients enhanced the lipophilicity. Amino, cyano group on ring B and the bridging S, SO, SO 2 with their negative coefficients showed an adverse effect on the lipophilicity parameter. Thus, Kier-Hall E-state indices along with topological indices could be well applied for deriving QSPR models and analysing substitution effects of various functional groups. The training set, correlation matrix and observed and experimental log P values are available as supplementary material for this article.

Computational modeling studies on anti-HIV-1 non-nucleoside reverse transcriptase inhibition by dihydroalkoxybenzyloxopyrimidines analogues: an electrotopological atomistic approach

“…All the 74 compounds were sketched using V-life MDS software [41]. The inhibitory activity pIC 50 Electrotopological State (E-State) indices are widely used in QSAR modeling, including AIDS related research [21,43,44]. The large amount of variables in E-State Indices represent the structural characteristics of molecules such as information about their non-covalent interactions.…”

“…[18] Since then three more NNRTIs-nevirapine, delavirdine and efavirenz have been approved for the treatment of HIV-1 and a few more are in clinical development, including rilpivirine, etravirine and dapivirine [19]. Till date various molecular modelling studies have been performed using QSAR [20], QSPR [21], Simple docking [22] and Template docking [23] on some NNRTIs.…”

A group center overlap based approach for “3D QSAR” studies on TIBO derivatives

“…A certain number of computational techniques have been found useful for the establishment of these QSAR such as multiple linear regression (MLR), 46,47 GFA, 48 and CoMFA. 49 A relatively recent technique and the one that shows considerable promise is that of artificial neural networks (ANN).…”

Assessing ligand efficiencies using template-based molecular docking and Tabu-clustering on tetrahydroimidazo-[4,5,1-jk][1,4]-benzodiazepin-2(1H)-one and-thione (TIBO) derivatives as HIV-1RT inhibitors

“…20,21 In QSAR methodologies, a mathematical relationship, relating the biological activity to some molecular descriptors is obtained. [22][23][24] In docking studies, different search algorithms such as simulated annealing and genetic algorithm in combination with scoring function such as molecular mechanic calculations are being used to study the binding of the candidate ligands to an enzyme with known structure. Through docking procedures, not only new biological active compound is introduced, but also the chemistry of the ligandenzyme interaction is well recognized.…”