Residue‑resolved dynamically averaged interaction analysis of direct factor Xa inhibitors by MD‑FMO combination calculations
Abstract
Four widely used direct oral anticoagulants (DOACs)-Edoxaban, Betrixaban, Apixaban, and Rivaroxaban-inhibit factor Xa, a key enzyme in the blood coagulation cascade. Despite their pharmacological importance, theoretical analyses of their binding modes with factor Xa remain limited. In this study, we performed fragment molecular orbital (FMO) calculations to quantitatively analyze inhibitor-protein interactions. Structural ensembles were obtained from molecular dynamics (MD) simulations employing classical force fields. Interaction energies between each ligand and the amino acid residues in the binding pocket region were dynamically averaged over MD-derived structural fluctuations. Comparative analyses revealed both common and distinct binding features among the four inhibitors at residue-level resolution. As a result, Cys191, Tyr99, Trp215, Glu217, Phe174, and Gln192 were identified as major contributive residues across the four ligands, with cooperative stabilization arising from electrostatic, charge-transfer, and dispersion components. The influence of protonation (charged states) was also examined for Edoxaban and Betrixaban.
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