Background:
Despite the introduction of direct oral anticoagulants, the search for new oral anticoagulants remains an urgent task.
Objective:
Using the docking and scoring, based on physical methods, simple chemical rules, methods of synthesis and activity measurement, to develop new low-molecular-weight inhibitors of factor Xa, which are potential anticoagulants.
Method:
The development of leads was based on chemical synthesis and the structure-based drug design methods. The basic idea is to combine the two approaches: one based on predictive modeling, and the other – on the experimental data.
Results:
In frame of our concept 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, screening, chemical synthesis and activity measurement. However, the most time – consuming process in this method (chemical synthesis) was decided to simplify and reduce the cost to the extent that it could be allowed: a very simple chemical reaction was chosen - the formation of an amide bond.
Conclusion:
In this work, we demonstrated how, using simple chemical rules, based on the structure-based drug design, substances with a nanomolar concentration of activity can be developed. Using our method, we developed substances with nanomolar concentration of activity. Further chemical modification of this leads improved the inhibition constant by more than one order.