Pharmacophore and QSAR Modeling of Neuronal Nitric Oxide Synthase Ligands and Subsequent Validation and In Silico Search for New Scaffolds.

UNLABELLED: Neuronal Nitric Oxide synthase (nNOS) is an attractive challenging target for the treatment of various neurodegenerative disorders. To date, several structure-based studies were conducted to search novel selective nNOS inhibitors. OBJECTIVE: Discovery of novel nNOS lead scaffolds through the integration of ligand-based threedimensional (3D) pharmacophore (s) with quantitative structure-activity relationship model. METHOD: The pharmacophoric space of ten structurally diverse sets acquired from 145 previously reported nNOS inhibitors was scrutinize to fabricate representative pharmacophores. Afterwards, genetic algorithm together with multiple linear regression analysis was applied to find out an optimal pharmacophoric models and 2D physicochemical descriptors able to produce optimal predictive QSAR equation (r(2) 116 =0.76, F = 353, r(2) LOO = 0.69, r(2) PRESS against 29 external test ligands =0.51). A minimum of three binding modes between ligands and nNOS binding pocket rationalized by the emergence of three pharmacophoric models in the QSAR equation were illustrated. The QSAR-selected pharmacophores were validated by receiver operating characteristic curves analysis and afterward invested as a tool for screening national cancer institute (NCI) database. RESULTS: Low micro molar novel nNOS inhibitors were revealed. CONCLUSION: Two structurally diverse compounds 148 and 153 demonstrated new scaffolds toward the discovery of potent nNOS inhibitors.

Design, Synthesis and in Vivo Evaluation of Novel Glycosylated Sulfonylureas as Antihyperglycemic Agents.

Sulphonylurea compounds have versatile activities such as antidiabetic, diuretic, herbicide, oncolytic, antimalarial, antifungal and anticancer. The present study describes the design, synthesis and in vivo testing of novel glycosylated aryl sulfonylurea compounds as antihyperglycaemic agents in streptozocine-induced diabetic mice. The rational for the introduction of the glucosamine moiety is to enhance selective drug uptake by pancreatic ß-cells in order to decrease the cardiotoxic side effect commonly associated with sulfonylurea agents. 2-Deoxy-2-(4-chlorophenylsulfonylurea)-D-glucopyranose was found to be the most potent antihyperglycaemic agents among the synthesized compounds in diabetic mice. This investigation indicates the importance of this novel class as potential antihyperglycaemic agents.

Recent progress in prostate-specific antigen and HIV proteases detection.

Proteases mediate a wide variety of biological events and have a critical role in the development of many diseases. Protease detection methods can be hindered by the limitation of assay safety, sensitivity, specificity, time constraints and ease of on-site analysis. Notably, the implementation of various detection methods on biosensing platforms translates them into practical biosensing applications. Currently, the detection of prostate cancer and AIDS at the earliest occasion is one of the major research obstacles. Therefore, recent advances focus on the development of portable detection systems toward point-of-care testing. These detection systems should be highly sensitive and specific for the detection of their prognostic biomarkers, such as the prostate-specific antigen and HIV load assay for prostate cancer and AIDS, respectively. These methods will also facilitate decision-making on a treatment regimen.

Extensive ligand-based modeling and in silico screening reveal nanomolar inducible nitric oxide synthase (iNOS) inhibitors.

Inducible nitric oxide synthase (iNOS) has been implicated in a variety of diseases prompting several attempts to discover and optimize new iNOS inhibitors. Accordingly, we explored the pharmacophoric space of 143 iNOS inhibitors. Subsequently, genetic algorithm and multiple linear regression analysis were employed to select an optimal combination of pharmacophoric models and 2D physicochemical descriptors to produce self-consistent quantitative structure-activity relationship (QSAR) of optimal predictive potential (correlation coefficient r115=0.83, F=23.92, r²(LOO)=0.61, r²(PRESS) against 28 external test inhibitors=0.51). Two orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least two binding modes accessible to ligands within iNOS binding pocket. The pharmacophores were validated by comparison with crystallographic complexes of active iNOS inhibitors and receiver operating characteristic (ROC) curves analysis. We employed the pharmacophoric models and associated QSAR equation to screen the national cancer institute list of compounds (NCI). Three low nanomolar inhibitors were identified. The most potent hit exhibited irreversible inhibition of iNOS with IC50 value of 1.4 nM.