• Neelima Sapre

      Articles written in Journal of Chemical Sciences

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

      Nitin S Sapre Nilanjana Pancholi Swagata Gupta Arun Sikrwar Neelima Sapre

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      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 ($R^2 = 0.948$, $R^2_{\text{adj}} = 0.939$, $SE = 0.177$, $F$-ratio = 101.22). The results of the test set too implicated a good fit ($R^2 = 0.941$, $R^2_{\text{adj}} = 0.929$, $SE = 0.157$, $F$-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, SO2 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.

    • 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

      Nitin S Sapre Swagata Gupta Neelima Sapre

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      A template-based flexible docking simulation followed by `Tabu-clustering’ was performed on a series of 38 TIBO derivatives as HIV-1 reverse transcriptase (HIV-1 RT) inhibitors. Four different templates of the Cl-TIBO (1-REV) were created and used as reference templates for docking and aligning. On the basis of the optimal conformation of the ligands, when fitting to the template, the respective scoring functions were obtained; different ligand efficiencies were evaluated and analysed. Statistical modelling using artificial neural network (ANN: $r^2 = 0.922$) and multiple linear regression method (MLR: $r^2 = 0.851$) showed good correlation between the biological activity, binding affinity, and different ligand efficiencies of the compounds, which suggest the robustness of the template-based binding conformations of these inhibitors. Our studies suggest that, template-based docking followed by ‘Tabuclustering’ will give a better alignment of inhibitors with respect to the crystal coordinates and enhance the docking efficiency. Also, our study indicates that scoring functions based on 3D symmetry analysis along with heavy atoms count serve as a valuable tool for estimating the efficiency of the ligands. Thus, this is a novel method based on heavy atoms count predicting the binding affinity of the TIBO group of inhibitors, so that their therapeutic utility can be enhanced.

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