Molecular dynamics simulation of the inhibition mechanism of factor XIa by Milvexian-like macrocyclic inhibitors

Abstract

Factor XIa is an important coagulation factor in the coagulation cascade, and its inhibitors have become a hot topic of research for their potential to block thrombus formation without increasing the risk of bleeding. In this paper, molecular dynamics simulation and binding free energy calculation methods were used to study the inhibition mechanism of five macrocyclic competitive inhibitors, which are the same as the Milvexian nucleus. And the reasons for the different inhibitory abilities of the inhibitors with different substituents in the nucleus were summarized. When the inhibitor has a triazole at the head or a carbamate at the tail, it can enhance the hydrogen bonding or electrostatic interaction with its nearby polar residues. The inhibitor 8 with –CH3 in the tail interacts less with its surrounding residues than the inhibitors 13 and 17 with -CHF2 when both heads carry triazoles. The triazole of inhibitor 17 bears a Cl atom, which can form a strong hydrophobic interaction with the nearby disulfide bond. In addition, the nitrogen atom on the ketone ring of this inhibitor can also increase its interaction with nearby residues. Therefore, inhibitor 17 has the strongest affinity to the protein. The present work has implications for the design of more efficient anticoagulant drugs for FXIa macrocyclic inhibitors.