Design and development of topoisomerase inhibitors using molecular modelling studies

Journal of Chemical Biology

Muthu K. Kathiravan¹  Madhuri A. Nagras¹  Madhavi M. Khilare¹  Aparna S. Chothe¹ 

[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

关键词: Pharmacophore;    3D-QSAR;    Docking;    Topoisomerases inhibitor;    Pyridine;   

DOI  :  10.1007/s12154-012-0079-9

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

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 (r2 = 0.7892, SD = 0.2948, F = 49.9, P = 1.379). The test set correlation is characterized by PLS factors (q2 = 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.

【 授权许可】

Unknown