An Unexpected Dynamic Binding Mode between Coagulation Factor X and Rivaroxaban Reveals Importance of Flexibility in Drug Binding

: Rivaroxaban (RIV) is a direct oral anticoagulant (DOAC) targeting activated coagulation factor X (FXa). An earlier study reported the F174A mutant of FXa resistant to a RIV-like inhibitor, Apixaban. In current study, the detailed molecular mechanism of the resistance has been explored by molecular dynamics simulations on the impaired interactions between RIV and FXa in the damaged S4 pocket of F174A mutant. Besides, an unexpected relative stable binding mode of S1'S1 was revealed, which required dynamic motions of Gln192 and Gln61 to allow the morpholinone moiety of RIV to shift into the S1' pocket and form strong interactions. These dynamic motions of RIV and critical residues might be important in drug design for direct inhibitors of coagulation factors.