Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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Characterization of Binding Mode for Human Coagulation Factor XI (FXI) Inhibitors

  • Cho, Jae Eun (Graduate School of New Drug Discovery and Development, Chungnam National University) ;
  • Kim, Jun Tae (Graduate School of New Drug Discovery and Development, Chungnam National University) ;
  • Jung, Seo Hee (Graduate School of New Drug Discovery and Development, Chungnam National University) ;
  • Kang, Nam Sook (Graduate School of New Drug Discovery and Development, Chungnam National University)
  • Received : 2012.01.14
  • Accepted : 2013.01.28
  • Published : 2013.04.20
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Abstract

The human coagulation factor XI (FXI) is a serine protease that plays a significant role in blocking of the blood coagulation cascade as an attractive antithrombotic target. Selective inhibition of FXIa (an activated form of factor XI) disrupts the intrinsic coagulation pathway without affecting the extrinsic pathway or other coagulation factors such as FXa, FIIa, FVIIa. Furthermore, targeting the FXIa might significantly reduce the bleeding side effects and improve the safety index. This paper reports on a docking-based three dimensional quantitative structure activity relationship (3D-QSAR) study of the potent FXIa inhibitors, the chloro-phenyl tetrazole scaffold series, using comparative molecular field analysis (CoMFA) and comparative molecular similarity analysis (CoMSIA) methods. Due to the characterization of FXIa binding site, we classified the alignment of the known FXIa inhibitors into two groups according to the docked pose: S1-S2-S4 and S1-S1'-S2'. Consequently, highly predictive 3D-QSAR models of our result will provide insight for designing new potent FXIa inhibitors.

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