Quantitative structureactivity relationship (QSAR) studies have been performed on some non-benzodiazepine series of benzodiazepine receptor (BZR) ligands, namely a series of thienylpyrazologuinolines and a series of imidazoquinoxalines. Studies reveal the merits and demerits of the substituents and their physicochemical properties in each case, in addition to the essential requirements for the binding for each type of ligand.

At present, chemotherapy seems to be the main weapon in the arsenal of remedies for the ongoing crusade against AIDS. The mode of binding of the TIBO family of inhibitors has been of interest because these compounds do not fit the two-hinged-ring model as generally observed in the NNRTIs. Flexible docking simulations were performed with a series of 53 TIBO derivatives as NNRTIs. Binding preferences as well as the structural and energetic factors associated with them were studied. A good correlation (r(2)=0.849, q(2)=0.843) was observed between the biological activity and binding affinity of the compounds which suggest that the identified binding conformations of these inhibitors are reliable. Further screening of PubChem database yielded novel scaffolds. Our studies suggest that modifications to the TIBO group of inhibitors might enhance their binding efficacy and hence, potentially, their therapeutic utility.

PrefaceThis Part II of the hot topic issue on Advances in the Studies of Anti-HIV Drugs contains articles mainly related to integrase inhibitors. Presently, the reverse transcriptase (RT) and protease inhibitors, that have been mainly described in Part I, are used in combination to effectively treat the HIV-1 infection. Though this combination therapy has exhibited multiple clinical benefits, the emergence of resistance highlights the need of new anti-HIV agents. Consequently, the researchers focused their attention on new agents able to interfere with additional steps of viral replication and one of them, found to be most crucial, is the integration of the viral DNA into the host cell genome. This step is catalyzed by the enzyme integrase (IN). In the very first article of this issue, Soultrait et al. discuss a combination therapy of RT and IN inhibitors that is based on peptides. Though peptides have long been considered as poor drug candidates, current knowledge on improving the stability and bioavailability of these agents may lead to the effective use of peptides in therapy. Integrase Inhibitors have lately drawn great attention of the chemists and so three most comprehensive articles (2-4), covering all uptodate developments in the area have been fetched. In article 2, Gupta and Nagappa have reviewed all different categories of IN inhibitors, pointing out in each category the important structural features that may be essential for IN inhibition. On the other hand, in article 3, Maurin et al. have presented a detailed study on SARs of these inhibitors and their modes of interaction with the enzyme, and in article 4, Parrill has highlighted even more critically the binding sites, SARs, and future prospectives of these IN inhibitors.In the last article (article 5), Anatasi et al. discuss new antiviral nucleoside prodrugs which have been developed in recent years, so as to improve the efficacy of a given antiviral drug or to overcome several drug deficiencies. Examples of carrierlinked nucleoside prodrugs or nucleoside bioprecursors have been presented and their active mechanism discussed. Thus, this issue covers 5 excellent articles, which I found quite stimulating and informative and hope that the readers will also enjoy reading them. I heartily acknowledge the interest and the zeal that the authors have shown in contributing these articles.

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.

Current challenges in drug designing and lead optimization has reached a bottle neck where the main onus lies on rigorous validation to afford robust and predictive models. In the present study, we have suggested that predictive structure-activity relationship (SAR) models based on robust statistical analyses can serve as effective screening tools for large volume of compounds present either in chemical databases or in virtual libraries. 3D descriptors derived from the similarity-based alignment of molecules with respect to group center overlap from each individual template point and other "alignment averaged," but significant descriptors (ClogP, molar refractivity, connolly accessible area) were used to generate QSAR models. The results indicated that the artificial neural network method (r(2) = 0.902) proved to be superior to the multiple linear regression method (r(2) = 0.810). Cross validation of the models with an external set was reasonably satisfactory. Screening PubChem compound database based on the models obtained, yielded 14 newer modified compounds belonging to the TIBO class of inhibitors, as well as, two novel scaffolds, with enhanced binding efficacy as hits. These hits may be targeted toward potent lead-optimization and help in designing and synthesizing new compounds with potential therapeutic utility.

In 2008, India launched a flagship national health insurance programme, the Rashtriya Swasthya Bima Yojana (RSBY) for those living below the poverty line (BPL). 1 Using qualitative methods and thematic analysis, this exploratory study of poor women from three selected districts of West Bengal sought to gauge reasons for low registration and factors affecting choice of institutional healthcare among those who had registered for the RSBY. In particular, we sought to understand the underlying factors, if any, which affect judgements on institutional healthcare.

Quantitative structure-activity relationships (QSAR), based on E-state indices have been developed for a series of tetrahydroimidazo-[4,5,1-jk]-benzodiazepinone derivatives against HIV-1 reverse transcriptase (HIV-1 RT). Statistical modeling using multiple linear regression technique in predicting the anti-HIV activity yielded a good correlation for the training set (R(2) = 0.913, R(2)(adj) = 0.897, Q(2) = 0.849, MSE = 0.190, F-ratio = 59.97, PRESS = 18.05, SSE = 0.926, and p value = 0.00). Leave-one-out cross-validation also reaffirmed the predictions (R(2) = 0.850, R(2)(adj) = 0.824, Q(2) = 0.849, MSE = 0.328, and PRESS = 18.05). The predictive ability of the training set was also cross-validated by a test set (R(2) = 0.812, R(2)(adj) = 0.799, Q(2) = 0.765, MSE = 0.347, F-ratio = 64.69, PRESS = 7.37, SSE = 0.975, and p value = 0.00), which ascertained a satisfactory quality of fit. The results reflect the substitution pattern and suggest that the presence of a bulky and electropositive group in the five-member ring and electron withdrawing groups in the seven-member ring will have a positive impact on the antiviral activity of the derivatives. Bulky groups in the six-member ring do not show an activity-enhancing impact. Outlier analysis too reconfirms our findings. The E-state descriptors indicate their importance in quantifying the electronic characteristics of a molecule and thus can be used in chemical interpretation of electronic and steric factors affecting the biological activity of compounds.

Researchers are on the constant lookout for new antiviral agents for the treatment of AIDS. In the present work, ligand based modeling studies are performed on analogues of substituted phenyl-thio-thymines, which act as non-nucleoside reverse transcriptase inhibitors (NNRTIs) and novel leads are extracted. Using alignment-dependent descriptors, based on group center overlap (SALL, HDALL, HAALL and RALL), an alignment-independent descriptor (S log P), a topological descriptor (Balaban index (J)) and a 3D descriptor dipole moment (μ) and shape based descriptors (Kappa 2 index ((2)κ)), a correlation is derived with inhibitory activity. Linear and non-linear techniques have been used to achieve the goal. Support Vector Machine (SVM, R = 0.929, R(2) = 0.863) and Back Propagation Neural Network (BPNN, R = 0.928, R(2) = 0.861) methods yielded near similar results and outperformed Multiple Linear Regression (MLR, R = 0.915, R(2) = 0.837). The predictive ability of the models are cross-validated using a test dataset (SVM: R = 0.846, R(2) = 0.716, BPNN: R = 0.841, R(2) = 0.707 and MLR: R = 0.833, R(2) = 0.694). It is concluded that the hydrophobicity (S log P) and the polarity (μ) of a ligand and the presence of hydrogen donor (HDALL) moieties are the deciding factors in improving antiviral activity and pharmaco-therapeutic properties. Based on the above findings, a virtual dataset is created to extract probable leads with reasonable antiviral activity as well as better pharmacophoric properties.