Computational Investigations of Coumarin Derivatives as Cyclindependent Kinase 9 Inhibitors Using 3D-QSAR, Molecular Docking and Molecular Dynamics Simulation.

Background: Cyclin-dependent Kinase 9 as one of the serine/threonine protein kinases has become an important target for the treatment of cancer especially driven by transcriptional dysregulation.

Objective: This thesis was conducted to elucidate the structure-activity relationship and interaction mode of coumarin compounds acting on CDK9.

Methods: Three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics simulation were conducted to reveal the structural requirements for bioactivities. The 3D-QSAR model was constructed to find the features required for different substituents on the coumarin scaffold. Molecular docking and molecular dynamics simulation were employed to generate the binding mode and stability of CDK9.

Results: The Q2 and R2 values of the CoMFA model were calculated as 0.52 and 0.999, while those for the CoMSIA model were 0.606 and 0.998. It is believed that the significant statistical parameters of CoMFA and CoMSIA models revealed high activity-descriptor relationship efficiency. Therefore, we considered the 3D-QSAR model to be robust and accurate. The contour maps provided a deep structure-activity relationship and valuable clues for rational modification. Based on the contour maps, 4 novel CDK9 inhibitors which were predicted to have satisfactory pharmacokinetic characteristics were designed and exhibited better-predicted activities. Subsequently, molecular docking was employed to generate the binding mode of CDK9. Furthermore, 50 ns MD simulation was of great help in verifying the accuracy of docking results and the stability of the complexes.

Conclusion: The study is a valuable insight for further research on novel and effective inhibitors targeting CDK9.