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; Factor Xa (FXa); antithrombotic agents; antithrombotic drug; direct oral anticoagulant; drug design methods.
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