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Predicting anti-HIV activity of 1,1,3-trioxo[1,2,4]-thiadiazine (TTD) derivatives: 3D QSAR approach

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Abstract

Human immunodeficiency virus type 1 (HIV-1) is the pathogenic retrovirus and causative agent of acquired immunodeficiency syndrome (AIDS). HIV-1 reverse transcriptase (RT) is one of the key enzymes in the duplication of HIV-1. Inhibitors of HIV-1 RT are classified as nonnucleoside reverse-transcriptase inhibitors (NNRTIs) and nucleoside reverse-transcriptase inhibitors (NRTIs). NNRTIs bind in a region not associated with the active site of the enzyme. Within the NNRTIs category, there is a set of inhibitors commonly referred to as 1,1,3-trioxo-thiadiazine (TTD) derivatives. Based on the structures and biodata of previous TDS analogs, three-dimensional (3D) quantitative structure–activity relationship (QSAR) studies have been performed which resulted in two reliable computational models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) with r 2 values of 0.883 and 0.852 and q 2 values of 0.639 and 0.608, respectively. The predictive ability of the developed CoMFA and CoMSIA models was also confirmed by using a test (external validation) set comprised of eight molecules, with predicted r 2 value of 0.832 and 0.760, respectively. It is shown that the steric and electrostatic properties predicted by CoMFA contours and hydrophobic properties predicted by CoMSIA contours can be related to anti-HIV activity. These models are a significant guide to trace the features that really matter, especially with respect to design of novel compounds.

Graphical abstract

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) of 1,1,3-trioxo-thiadiazine (TTDs) derivatives. The parameters indicated are responsible for increasing anti-HIV activity.

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Acknowledgments

We would like to thank Prof. B. Suresh, Principal, J.S.S. College of Pharmacy, Ooty (TN), India for providing access to the computational resources and one of the authors (V.R.) is thankful to AICTE for providing a (QIP) fellowship.

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Authors and Affiliations

  1. Pharmaceutical Chemistry Research Laboratory, Department of Pharmaceutical Sciences, Dr. H. S. Gour Vishwavidyalaya, Sagar, 470 003, MP, India

    Veerasamy Ravichandran & Ram Kishore Agrawal

  2. Department of Pharmaceutical Chemistry, J. S. S. College of Pharmacy, Ooty, TN, India

    Bommenahath Ravanappa PrashanthaKumar & Sundaram Sankar

Authors
  1. Veerasamy Ravichandran
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  2. Bommenahath Ravanappa PrashanthaKumar
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  3. Sundaram Sankar
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  4. Ram Kishore Agrawal
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Correspondence to Ram Kishore Agrawal.

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Ravichandran, V., PrashanthaKumar, B.R., Sankar, S. et al. Predicting anti-HIV activity of 1,1,3-trioxo[1,2,4]-thiadiazine (TTD) derivatives: 3D QSAR approach. Med Chem Res 18, 511–522 (2009). https://doi.org/10.1007/s00044-008-9145-9

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