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Combined Molecular Dynamics and Docking Studies on Direct Oral Anticoagulant Binding to Factor Xa Variants

1Div. Thrombosis and Hemostasis, Einthoven Laboratory, for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands, Rotterdam, Zuid-Holland, Netherlands, 2AIMMS Division of Molecular and Computational Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands;, Amsterdam, Noord-Holland, Netherlands, 3Centenary Institute, University of Sydney, Sydney, New South Wales, Australia, 41VarmX, Leiden, The Netherlands. 2Division of Thrombosis and Hemostasis, Einthoven Laboratory for Vascular and Regenerative Medicine, Leiden University Medical Center, Leiden, The Netherlands., Leiden, Zuid-Holland, Netherlands, 5AIMMS Division of Molecular and Computational Toxicology, Department of Chemistry and Pharmaceutical Sciences, Vrije Universiteit, Amsterdam, The Netherlands, Amsterdam, Noord-Holland, Netherlands, 6Leiden University Medical Center

Abstract Number: PB0564

Meeting: ISTH 2022 Congress

Theme: Coagulation and Natural Anticoagulants » Coagulation Factors and Inhibitors

Background: For prevention and/or treatment of bleeding complications related to factor (F)Xa-inhibiting direct oral anticoagulants (DOACs) specific reversal agents are required. Previously, we generated F174-substituted human FX variants that demonstrated decreased sensitivity towards FXa-DOACs. Our strategy for developing these bypassing FX variants relied on disruption of the FXa-inhibitor binding site. While the latter was demonstrated employing Molecular Dynamics (MD) simulations, these studies did not quantitatively resolve to what extent the FXa-inhibitor binding affinity was affected by the F174-substitution.

Aims: Develop an in silico approach to assess differences in FXa-inhibitor binding affinity between wild-type and substituted FXa using combined molecular docking and MD simulations.

Methods: Starting from a crystal structure of wild-type FXa and using PDB-tools, the hydrogen prediction tool Protoss, and the AMBER biomolecular simulation package, conformations of wild-type and substituted FXa variants were efficiently generated by employing an accelerated MD protocol on ns time scales. These conformations were used as template for subsequent FXa-apixaban docking and scoring.

Results: Using our combined MD/docking approach, the effect of F174-substitutions on apixaban binding was evaluated. No substantial differences in atom-positional root-mean-square deviations (RMSDs) were observed during simulations of either wild-type or F174-substituted FXa, indicating that FXa stability was preserved following F174-substitution. In contrast, the number of conformational clusters generated from accelerated MD simulation differed among the simulations, suggesting reduced conformational flexibility of the variants. Preliminary docking to initial conformations of FXa indicated loss in binding affinity of apixaban for F174A-FXa and F174S-FXa.

Conclusion(s): Our approach was used to identify possibly reduced FXa binding for apixaban in silico that is consistent with earlier in vitro observations for FXa variants with decreased sensitivity towards apixaban. Overall, our combined MD and molecular docking simulation strategy can be used to explore the binding of FXa-DOACs to modified FXa variants.

To cite this abstract in AMA style:

Veizaj D, Poole III D, Schreuder M, Reitsma P, Verhoef D, Geerke D, Bos M. Combined Molecular Dynamics and Docking Studies on Direct Oral Anticoagulant Binding to Factor Xa Variants [abstract]. https://abstracts.isth.org/abstract/combined-molecular-dynamics-and-docking-studies-on-direct-oral-anticoagulant-binding-to-factor-xa-variants/. Accessed September 21, 2023.

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