Discovery of FIXa inhibitors by combination of pharmacophore modeling, molecular docking, and 3D-QSAR modeling

Abstract

Human Coagulation Factor IXa (FIXa), specifically inhibited at the initiation stage of the blood coagulation cascade, is an excellent target for developing selective and safe anticoagulants. To explore this inhibitory mechanism, 86 FIXa inhibitors were selected to generate pharmacophore models and subsequently SAR models. Both best pharmacophore model and ROC curve were built through the Receptor–Ligand Pharmacophore Generation module. CoMFA model based on molecular docking and PLS factor analysis methods were developed. Model propagations values are q² = 0.709, r² = 0.949, and r²_pred = 0.905. The satisfactory q² value of 0.609, r² value of 0.962, and r²_pred value of 0.819 for CoMSIA indicated that the CoMFA and CoMSIA models are both available to predict the inhibitory activity on FIXa. On the basis of pharmacophore modeling, molecular docking, and 3D-QSAR modeling screening, six molecules are screened as potential FIXa inhibitors.

Keywords:

• Pharmacophore
• molecular docking
• 3D-QSAR
• FIXa
• antithrombotic

Acknowledgments

Authors thank Kunming Institute of Botany, Chinese Academy of Sciences for providing computational and laboratory facilities.

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

This work was financially supported by CAS ‘Light of West China’ Program ([2014]91 to Z.Z.; Y8252211W1 to L.L. Wang), CAS Strategic biological resources service network [ZSTH-021], the Strategic Priority Research Program of the Chinese Academy of Sciences [Grant No. XDA12030206], and National Natural Science Foundation of China [No. 21772207].