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Pyridones as NNRTIs against HIV-1 mutants: 3D-QSAR and protein informatics

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Abstract

CoMFA and CoMSIA based 3D-QSAR of HIV-1 RT wild and mutant (K103, Y181C, and Y188L) inhibitory activities of 4-benzyl/benzoyl pyridin-2-ones followed by protein informatics of corresponding non-nucleoside inhibitors’ binding pockets from pdbs 2BAN, 3MED, 1JKH, and 2YNF were analysed to discover consensus features of the compounds for broad-spectrum activity. The CoMFA/CoMSIA models indicated that compounds with groups which lend steric-cum-electropositive fields in the vicinity of C5, hydrophobic field in the vicinity of C3 of pyridone region and steric field in aryl region produce broad-spectrum anti-HIV-1 RT activity. Also, a linker rendering electronegative field between pyridone and aryl moieties is common requirement for the activities. The protein informatics showed considerable alteration in residues 181 and 188 characteristics on mutation. Also, mutants’ isoelectric points shifted in acidic direction. The study offered fresh avenues for broad-spectrum anti-HIV-1 agents through designing new molecules seeded with groups satisfying common molecular fields and concerns of mutating residues.

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Abbreviations

NNRTIs:

Non-nucleoside reverse transcriptase inhibitors

QSAR:

Quantitative structure–activity relationship

CoMFA:

Comparative molecular field analysis

CoMSIA:

Comparative molecular similarity indices analysis

NNIBP:

Non-nucleoside inhibitors binding pocket

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Acknowledgments

Authors thank Dr. Shreekant Deshpande and V. Murugesan for helpful discussion and Ms. Neelam Mishra for technical help. Two of the authors, UD and SV, thank CSIR and DST, New Delhi, respectively, for senior research fellowships. CDRI Communication No.8492

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Authors and Affiliations

  1. Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226001, India

    Utsab Debnath, Saroj Verma, Surabhi Jain, Setu B. Katti & Yenamandra S. Prabhakar

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  1. Utsab Debnath
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  2. Saroj Verma
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  3. Surabhi Jain
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Correspondence to Yenamandra S. Prabhakar.

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Debnath, U., Verma, S., Jain, S. et al. Pyridones as NNRTIs against HIV-1 mutants: 3D-QSAR and protein informatics. J Comput Aided Mol Des 27, 637–654 (2013). https://doi.org/10.1007/s10822-013-9667-1

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