Abstract
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 Docking Server.
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.
Keywords: 3D-QSAR, 4, 5-Dihydro-1H-pyrazolo [4, 3-h] quinazoline, kinase inhibitors, Plk-1, CDK2/A, Aur-A, serine/ threonine protein kinase.
Graphical Abstract
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