Statistical Interaction Analysis Using Fragment Molecular Orbital (FMO) Calculations for Factor Xa Inhibitors

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 pharmacophore region were statistically evaluated, and the stabilizing interaction components were identified. Comparative analyses revealed both common and distinct binding features among the four inhibitors. 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.