In silico screening for identification of novel HIV-1 integrase inhibitors using QSAR and docking methodologies
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Med Chem Res DOI 10.1007/s00044-013-0490-y
ORIGINAL RESEARCH
In silico screening for identification of novel HIV-1 integrase inhibitors using QSAR and docking methodologies Pawan Gupta • Prabha Garg • Nilanjan Roy
Received: 10 October 2012 / Accepted: 11 January 2013 Ó Springer Science+Business Media New York 2013
Abstract Human immunodeficiency virus-1 integrase (HIV-1 IN) is an important target for HIV-1 infection. Here, shape based screening workflow was designed to discover novel inhibitors against HIV-1 IN protein. The best docked conformation of highly active curcumine molecule 32 (Gupta et al. Mol Diversity 15:733–750, 2011) was used as a template for screening of drug-like databases. The screened molecules were filtered out using toxicity studies. The in silico inhibitory activity of screened molecules against HIV-1 IN was predicted using 2D (Gupta et al. Curr Comput Aided Drug Des 9:141–150, 2013) and 3D (Gupta et al. Mol Diversity 15:733–750, 2011) QSAR models. Subsequently, putative binding modes of these molecules were investigated using different docking algorithms. Some of the molecules exhibited similar poses in both the algorithms and fulfilled the criteria for the best docking pose. Eventually, 11 novel scaffolds were identified from the designed workflow. These screened molecules could be potential hits against HIV-1 IN. These combined techniques were facilitated here to get different scaffolds with good ADMET, QSAR, and docking predictions, which can be further explored for lead optimization purpose. Besides, these scaffolds can be a good starting point
Electronic supplementary material The online version of this article (doi:10.1007/s00044-013-0490-y) contains supplementary material, which is available to authorized users. P. Gupta P. Garg (&) Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Mohali 160062, Punjab, India e-mail: [email protected]; [email protected] N. Roy Department of Biotechnology, National Institute of Pharmaceutical Education and Research (NIPER), Sector-67, S.A.S. Nagar, Mohali 160062, Punjab, India
for researchers for designing of new molecules against HIV-1 IN. Keywords HIV-1 IN Shape based screening Toxicity ADME QSAR predictions Docking
Introduction Acquired immune deficiency syndrome (AIDS) is an extremely serious condition, in which the body has very little defense against any sort of infection. Human immunodeficiency virus (HIV) is a causative agent of AIDS. The pol gene of HIV-1 encodes three essential enzymes, namely, reverse transcriptase (RT) (nucleoside and nonnucleoside), protease (PR), and integrase (IN) for replication of HIV. All of them are considered to be promising targets for the design and development of anti-HIV drugs. The intense research on RT and PR has been done for development of new therapeutic agents against HIV infection. Combinations of RT and PR inhibitors have been developed for therapeutic intervention, but most of them has limited effi
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