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 q(2) = 0.52, r(2) = 0.97 and r(2)(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.

• Authors: Ming Hao, Yan Li, Shu-Wei Zhang, Wei Yang
• Journal: Journal of enzyme inhibition and medicinal chemistry (J Enzyme Inhib Med Chem) Vol. 26 Issue 6 Pg. 792-804 (Dec 2011) ISSN: 1475-6374 [Electronic] England
• PMID: 21381886 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Thiophenes
• benzothiophene
• Factor IXa

Topics

• Binding Sites (drug effects)
• Databases, Factual
• Factor IXa (antagonists & inhibitors, metabolism)
• Humans
• Models, Molecular
• Molecular Dynamics Simulation
• Molecular Structure
• Quantitative Structure-Activity Relationship
• Thiophenes (chemistry, pharmacology)
• Thrombosis (drug therapy, metabolism)