Computational Strategies in Discovering Novel Non-nucleoside Inhibitors of HIV-1 RT

Abstract

A three-dimensional common feature pharmacophore model was developed using the X-ray structure of RT/non-nucleoside inhibitor (NNRTI) complexes. Starting from the pharmacophore hypothesis and the structure of the lead compound TBZ, new NNRTIs were designed and synthesized, having the benzimidazol-2-one system as a scaffold. Docking experiments showed that these molecules docked in a position and orientation similar to that of known inhibitors. Biological testing confirmed that our strategy was successful in searching for new leads as NNRTIs.

2D and 3D QSAR of Benzimidazole Analogues as Novel HIV-1 Non Nucleoside Reverse Transcriptase Inhibitors

“…[3][4][5] Literature survey has revealed that N1-aryl-benzimidazole analogues have significant potential as HIV-1 non-nucleoside reverse transcriptase inhibitors. [6][7][8][9][10][11][12] Molecular modeling study is an approach that is used to focus on the development of optimal models through variable selection and statistical methods to taper down to highly effective New Chemical Entities (NCE's). Quantitative Structure-Activity Relationships (QSAR) is a widely accepted tool used for finding associations between chemical structures and biological activity.…”

Synthesis and Antimicrobial Evaluation of Some Novel 2-(4-Chlorophenylimino) thiazolidin-4-one Derivatives

“…4-thiazolidinone derivatives are well known for their variety of pharmacological properties such as antibacterial, 1 anticonvulsant, 2 sedative, 3 antimycobacterial, 4,5 anti-tuberculosis, 6,7 anti-inflammatory, [8][9][10] anti-HIV, [11][12][13] anti tumor, 14 anti diabetic activity.…”

QSAR modeling of the inhibition of reverse transcriptase enzyme with benzimidazolone analogs

“…Several crystal structures of HIV-1 RT in the apo form and in complex with different NNRTIs were published and successful structure based design studies leading to the development of active NNRTIs have been reported (Mao et al, 2000). Ongoing effort in this direction 'hypothetical 3D pharmacophore model' for NNRTIs was built using a combined ligand-and structure-based molecular modeling approach consisting of five features: three hydrophobic groups, one hydrogen bond acceptor, and one hydrogen bond donor (Barreca et al, 2005). The postulated hypothesis produces a new class of NNRTIs as 1,3-dihydro-2H-benzimidazol-2-ones.…”

“…The present study reports the prediction of reverse transcriptase inhibition activities for 27 benzimidazolone compounds that include different functional groups, whose experimental data are available in the literature (Barreca et al, 2005(Barreca et al, , 2007Monforte et al, 2008). The purpose of present study is to perform a comparative quantitative structure activity relationship study using ERM (Mercader et al, 2008), as a novel variable selection search tool with FSWR (Draper and Smith 1981) and GFA (Rogers and Hopfinger 1994), a widely applied modeling strategy for the first time on the present data set of molecules.…”