Abstract
BackgroundThe discovery of clinically relevant inhibitors of HIV-RT for antiviral therapy has proven to be a challenging task. To identify novel and potent HIV-RT inhibitors, the quantitative structure–activity relationship (QSAR) approach became very useful and largely widespread technique forligand-based drug design.MethodsWe perform the two- and three-dimensional (2D and 3D) QSAR studies of a series of 1,2,3-thiadiazole thioacetanilides analogues to elucidate the structural properties required for HIV-RT inhibitory activity.ResultsThe 2D-QSAR studies were performed using multiple linear regression method, giving r2 = 0.97 and q2 = 0.94. The 3D-QSAR studies were performed using the stepwise variable selection k-nearest neighbor molecular field analysis approach; a leave-one-out cross-validated correlation coefficient q2 = 0.89 and a non-cross-validated correlation coefficient r2 = 0.97 were obtained. Docking analysis suggests that the new series have comparable binding affinity with the standard compounds.ConclusionsThis approach showed that hydrophobic and electrostatic effects dominantly determine binding affinities which will further useful for development of new NNRTIs.
Highlights
The discovery of clinically relevant inhibitors of human immunodeficiency virus (HIV)-reverse transcriptase (RT) for antiviral therapy has proven to be a challenging task
2D-quantitative structure–activity relationship (QSAR) The various 2D-QSAR models were developed using MLR method. 2D-QSAR equations were selected by optimizing the statistical results generated along with variation of the descriptors in these models
The randomization test shows confidence of approximately 99.9% that the generated model is not random and it is chosen as the QSAR model (Table 4)
Summary
The discovery of clinically relevant inhibitors of HIV-RT for antiviral therapy has proven to be a challenging task. Acquired immunodeficiency syndrome (AIDS), caused by human immunodeficiency virus (HIV) infection, is still one of the most important challenges for the chemotherapy of the early 21st century [1]. HIV RT is one of the three key enzymes in the HIV life cycle and the primary target of numerous anti-viral drug discovery efforts [4]. Due to the essential role of the HIV RT in the viral replication, the inhibition of RT is regarded as one of the most attractive targets in the anti-HIV chemotherapy [5]. Current anti-AIDS therapy is based on drugs that belong either to the class of nucleoside/nucleotide (NRTIs/ NtRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease, or entry inhibitors. NNRTIs are a structurally diverse group of compounds which interact with a specific allosteric non-substrate binding pocket site of HIV-1 RT (non-nucleoside inhibitor binding pocket), leading to a non-competitive inhibition of the enzyme [6]. NNRTIs are an important part of the successful combination therapy for HIV-1 known as highly active anti-retroviral therapy [8]
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