Investigation of the tight binding mechanism of a new anticoagulant DD217 to factor Xa by means of molecular docking and molecular dynamics

Abstract

A new promising drug candidate DD217 has been proposed recently as a potent anticoagulant acting on factor Xa (fXa) target. It exhibits the lowest concentration of doubling the prothrombin time among the known anticoagulants. In order to explain the efficacy of DD217 in terms of molecular interactions with its target we studied the hypothesis of the tight binding mechanism by means of molecular dynamics simulations and statistical analysis of the trajectory. The conducted analysis confirms the significant contributions to the MM/GBSA estimated binding free energy of the S4 pocket residues as well the crucial role of establishing the hydrogen bonds between the ligand and the backbone amides of Gly216 and Gly218 of the target. The simulation results support the hypothesis of the tight binding mechanism of DD217 to fXa.

Communicated by Ramaswamy H. Sarma

Keywords:

• Anticoagulant
• factor Xa inhibitor
• molecular modeling
• intermolecular interactions
• molecular dynamics
• binding mode
• MM/GBSA

Acknowledgments

The authors express their gratitude to business angel Mr. O.E. Balashov.

Disclosure statement

The authors report there are no competing interests to declare.

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article.

Additional information

Funding

This work was supported by business angel Mr. O.E. Balashov and ‘Skolkovo’ Foundation (Russian Federation) under Grant #G9/19.