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Design and development of topoisomerase inhibitors using molecular modelling studies.

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. FigureKey structural requirement for topoisomerase activity.

SUBMITTER: Kathiravan MK

PROVIDER: S-EPMC3536865 | biostudies-literature | 2012

REPOSITORIES: biostudies-literature

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Design and development of topoisomerase inhibitors using molecular modelling studies.

Kathiravan Muthu K MK Khilare Madhavi M MM Chothe Aparna S AS Nagras Madhuri A MA

Journal of chemical biology 20120929 1

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 ...[more]

PMID: 24078835

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Design and development of topoisomerase inhibitors using molecular modelling studies.

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Design and development of topoisomerase inhibitors using molecular modelling studies.

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