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Exploring the binding of HIV-1 integrase inhibitors by comparative residue interaction analysis (CoRIA)

Journal of Molecular Modeling volume 15, Article number: 233 (2009) Cite this article

Abstract

Since the recognition of HIV-1 integrase as a novel and rational target for HIV therapeutics, remarkable progress has been made in the development of integrase inhibitors. Computational techniques have played a critical role in accelerating research in this area. However, most previous computational studies were based solely on ligand information. In the present work, we describe the application of one of our recently developed receptor-based 3D-quantitative structure activity relationships (QSAR) methods, i.e. comparative residue interaction analysis (CoRIA), in exploring the events involved in ligand-integrase binding. In this methodology, the non-bonded interaction energies (van der Waals and Coulombic) of the inhibitors with individual active site residues of the integrase enzyme are calculated and, along with other thermodynamic descriptors, are correlated with biological activity using chemometric methods. Different combinations of descriptors were used to develop three types of QSAR models, all of which were found to be statistically significant by internal and external validation. This is the first report of such a dedicated receptor-based 3D-QSAR approach being applied to comprehend the integrase–inhibitor recognition process. In addition, the study was performed on 13-different series of inhibitors, thereby exploring the most structurally diverse data set ever used in understanding the inhibition of HIV-1 integrase. The major advantage of this technique is that it can quantitatively extract crucial residues and identify the nature of interactions between the ligand and receptor that modulate activity. The models suggest that Asp64, Thr66, Val77, Asp116, Glu152 and Lys159 are the key residues influencing the binding of ligands with the integrase enzyme, and the majority of these results are in line with earlier studies. The approach facilitates easy lead-to-hit conversion and design of novel inhibitors by optimisation of the interaction of ligands with these specific residues of the integrase enzyme.

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Acknowledgements

D.K.D thanks the All India Council of Technical Education (AICTE, New Delhi), J.V. thanks the Council of Scientific and Industrial Research (CSIR, New Delhi), and A.S. thanks the Indian National Science Academy (INSA, New Delhi) for financial support. The computational facilities were made possible through grants from the Department of Science and Technology (SR/FST/LSI-163/2003) and the Council of Scientific and Industrial Research (01(1986)/05/EMR-II).

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  1. Department of Pharmaceutical Chemistry, Bombay College of Pharmacy, Kalina, Santacruz (E), Mumbai, 400 098, India

    Devendra K. Dhaked, Jitender Verma, Anil Saran & Evans C. Coutinho

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Dhaked, D.K., Verma, J., Saran, A. et al. Exploring the binding of HIV-1 integrase inhibitors by comparative residue interaction analysis (CoRIA). J Mol Model 15, 233 (2009). https://doi.org/10.1007/s00894-008-0399-4

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  • DOI: https://doi.org/10.1007/s00894-008-0399-4

Keywords

  • CoRIA
  • Docking
  • G/PLS
  • HIV Integrase
  • QSAR