Title:Computational Investigations of Coumarin Derivatives as Cyclindependent
Kinase 9 Inhibitors Using 3D-QSAR, Molecular Docking and
Molecular Dynamics Simulation
Volume: 18
Issue: 5
Author(s): Sisi Liu, Yaxin Li*, Xilin Wei, Ran Zhang, Yifan Zhang and Chunyan Guo
Affiliation:
- Department of Pharmacy, Hebei North University, Zhangjiakou 075000, P.R. China
- Hebei Key Laboratory of Neuropharmacology, Hebei North University, Zhangjiakou 075000, P.R. China
Keywords:
Coumarin, CDK9, 3D-QSAR, molecular docking, molecular dynamics simulation, ADMET.
Abstract:
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.
