3d-QSAR studies on 4,5-dihydro-1h-pyrazolo [4,3-h] quinazolines as plk-1, cdk2/a and aur-a serine/threonine kinase inhibitors

Background: The family of serine/threonine protein kinases is associated with peculiar tumor cell-cycle checkpoints which are overexpressed in proliferating tissues as well as in cancers, making them as potential targets for cancer chemotherapy. In the present paper, 3D-QSAR studies were carried out on 4,5-dihydro-1H-pyrazolo[4,3-h]quinazolines against serine/threonine protein kinases viz. polo-like 1 (Plk-1), cyclin dependent 2/A (CDK2/A) and Aurora-A (Aur-A) and their in vitro anti-proliferative activity on A2780 ovarian cancer cell line. Methods: 3D-QSAR models were derived using stepwise forward-backward partial least square (SWFB_PLS) regression method using VlifeMDS QSAR plus software and the docking calculations were carried out using DockingServer. Results: The derived statistically significant and predictive 3D-QSAR models exhibited correlation coefficient r² in the range of 0.875 to 0.966 and predictive r² in the range of 0.492 to 0.618. The hydrogen bond donor NH group joining the phenyl ring with quinazoline and terminal amide group were found to favored for Plk-1, CDK2/A and anti-proliferative activity. Estimated energy of binding of compound 45 with enzymes was in the range of-8.52 to-9.03. Conclusion: The results of 3D-QSAR studies may be useful in the development of new pyrazolo[4,3-h]quinazoline derivatives with better inhibitory activities against serine/threonine kinases.