Comparative molecular field analysis and comparative molecular similarity indices analysis studies of α-ketothiazole arginine analogues inhibitors of coagulation factor XIa

Abstract

Factor XIa is a serine protease expressed as a zymogen that is converted to its active form, XIa, by factor XIIa and by thrombin, and plays a major role in amplification of thrombotic response to maintaining clot activity. The 3D-QSAR study of α-ketotiazole arginine analogue inhibitors of coagulation factor XIa were developed using CoMFA and CoMSIA models that showed excellent internal predictability and consistency, while validation using test-set compounds yielded a good predictive power for pIC₅₀. The CoMFA model with steric and electrostatic fields provided satisfactory statistical data (q² = 0.632 and q²_cv = 0.957) and CoMSIA model with steric, electrostatic, hydrophobic, H-bond donor and acceptor exhibited q² = 0.683 and q²_cv = 0.853. Interaction between receptor and ligands most importantly are H-bond hydrogens, salt bridge. The information obtained from both CoMFA and CoMSIA 3D contour maps may be used in the design of new coagulation factor XIa inhibitors.