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Design and development of topoisomerase inhibitors using molecular modelling studies

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Journal of Chemical Biology

Abstract

Topoisomerase inhibitors are used as anticancer and antibacterial agents. A series of novel 2,4,6-tri-substituted pyridine derivatives reported as topoisomerase inhibitors were used for quantitative structure–activity relationship (QSAR) study. In order to understand the structural requirement of these topoisomerase inhibitors, a ligand-based pharmacophore and atom-based 3D-QSAR model have been developed. A five-point pharmacophore with one hydrophobic group (H4), four aromatic rings (R5, R6, R7 and R8) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square (PLS) statistic results. The training set correlation is characterized by PLS factors (r 2 = 0.7892, SD = 0.2948, F = 49.9, P = 1.379). The test set correlation is characterized by PLS factors (q 2 = 0.7776, root mean squared error = 0.2764, Pearson R = 0.8926). The docking study revealed the binding orientations of these inhibitors at active site amino acid residues of topoisomerases enzyme. The results of pharmacophore hypothesis and 3D-QSAR provided the detail structural insights as well as highlighted the important binding features of novel 2,4,6-tri-substituted pyridine derivatives and can be developed as potent topoisomerase inhibitors.

Key structural requirement for topoisomerase activity

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Acknowledgments

The authors gratefully acknowledge the contributions of Prof. M. N. Navale, President, and Dr. (Mrs.) S. M. Navale, Secretary, Sinhgad Technical Education Society, Pune for constant motivation and encouragement.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, P. G. Research Centre, Sinhgad College of Pharmacy, S.No.44/1, Vadgaon (Bk), Off Sinhgad Road, Pune, 411041, Maharashtra, India

    Muthu K. Kathiravan, Madhavi M. Khilare, Aparna S. Chothe & Madhuri A. Nagras

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  1. Muthu K. Kathiravan
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  2. Madhavi M. Khilare
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  3. Aparna S. Chothe
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  4. Madhuri A. Nagras
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Correspondence to Muthu K. Kathiravan.

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Kathiravan, M.K., Khilare, M.M., Chothe, A.S. et al. Design and development of topoisomerase inhibitors using molecular modelling studies. J Chem Biol 6, 25–36 (2013). https://doi.org/10.1007/s12154-012-0079-9

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  • DOI: https://doi.org/10.1007/s12154-012-0079-9

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