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<p>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.</p>

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Residue‑resolved dynamically averaged interaction analysis of direct factor Xa inhibitors by MD‑FMO combination calculations

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Ryohei Yoshine,
  • Yoshinori Hirano,
  • Hideo Doi,
  • Shun Kitahara,
  • Kazuki Akisawa,
  • Koji Okuwaki,
  • Eiji Yamamoto,
  • Kenji Yasuoka,
  • Yuji Mochizuki

摘要

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.