Investigation on the binding mode of benzothiophene analogues as potent factor IXa (FIXa) inhibitors in thrombosis by CoMFA, docking and molecular dynamic studies

Abstract

Recently, benzothiophenes attract much attention of interest due to its possible inhibitory activity targeting FIXa, a blood coagulation factor that is essential for the amplification or consolidation phase of blood coagulation. To explore this inhibitory mechanism, three-dimensional quantitative structure–activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) studies on a series of 84 benzothiophene analogues, for the first time, were performed. As a result, a highly predictive CoMFA model was developed with the q² = 0.52, r² = 0.97 and r²_pred = 0.81, respectively. The CoMFA contour maps, the docking analysis, as well as the MD simulation results are all in a good agreement, proving the reliability and robustness of the model. These models and the information, we hoped, would be helpful in screening and development of novel drugs against thrombosis prior to synthesis.

Keywords::

• FIXa
• benzothiophene
• docking
• CoMFA
• MD

Acknowledgements

We are very grateful to Prof. Ling Yang for access to SYBYL software.

Declaration of interest

This work is financially supported by the National Natural Science Foundation of China (Grant No. 10801025).