3D-QSAR, Docking, and Molecular Dynamics Simulations Studies on Quinazoline Derivatives as PAK4 Inhibitors

Background: The p21-activated kinases 4 (PAK4) refer to a promising target for cancer treatment. Currently, a wide range of PAK4 inhibitors has been reported. Objective: The objective of this study is to study the structural requirements of quinoline derivatives as PAK4 inhibitors and to design novel PAK4 inhibitors. Method: In the present study, a set of quinazoline PAK4 inhibitors underwent CoMFA, CoMSIA, molecular docking, as well as molecular dynamics simulations. Results: The built CoMFA (q(2)=0.595, r(2)=0.986, r(pred)(2) =0.689) and CoMSIA (q(2)=0.762, r(2)=0.984, r(pred)(2)=0.822 ) models exhibited high robustness and prominent predicting ability. As revealed from the results of molecular docking and molecular dynamics simulations, hydrogen bond and hydrophobic interactions primarily impact the affinity of PAK4 inhibitors, and Leu398 acts as an amino acid that leads to significant stabilization of the mentioned inhibitors. Moreover, the present study developed five novel molecules exhibiting high biological activity predicted and satisfactory ADME properties. Conclusion: The structural basis of PAK4 with respect to the activities of its inhibitors was revealed, which may be conducive to designing novel PAK4 inhibitors.