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.