Abstract

Background: Despite the introduction of direct oral anticoagulants, the search for new oral anticoagulants remains an urgent task.

Objective: By using docking and scoring, based on physical methods, simple chemical rules, methods of synthesis, and activity measurement, develop new low-molecular-weight inhibitors of factor Xa, which are potential anticoagulants.

Methods: The development of leads was based on chemical synthesis and structure-based drug design methods. The basic idea was to combine the two approaches: one based on predictive modeling and the other based on the experimental data.

Results: In this study, we developed some nanomolar leads. Further chemical modification improved the inhibition constant by more than one order.

Discussion: The method proposed in this paper, as well as other methods, includes virtual screening, chemical synthesis, and activity measurement. However, the most time–consuming process in this method (chemical synthesis) was simplified, and the cost was reduced to the extent that was allowed; a very simple chemical reaction was chosen, i.e., the formation of an amide bond.

Conclusion: In this work, we demonstrated how using simple chemical rules based on the structurebased drug design, substances with a nanomolar concentration of activity can be developed.

Keywords: Chemical amide synthesis, antithrombotic drug, direct oral anticoagulant, drug design methods, Factor Xa (FXa), antithrombotic agents.

Graphical Abstract