Design and development of topoisomerase inhibitors using molecular modelling studies

• Published in: Journal of chemical biology Vol. 6; no. 1; pp. 25 - 36
• Main Authors: Kathiravan, Muthu K., Khilare, Madhavi M., Chothe, Aparna S., Nagras, Madhuri A.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 2013; Springer Nature B.V
• Subjects: Biochemistry; Biological and Medical Physics; Biophysics; Cell Biology; Chemistry; Chemistry and Materials Science; Inhibitor drugs; Molecular structure; Original; Original Article; Pharmacology; Pharmacology/Toxicology; Physical Chemistry; 3D-QSAR; Docking; Pyridine; Topoisomerases inhibitor; Pharmacophore
• ISSN: 1864-6158; 1864-6166
• DOI: 10.1007/s12154-012-0079-9

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.
Figure
Key structural requirement for topoisomerase activity