The Synthesis And Molecular Simulation Of Anticoagulants Factor XA Inhibitors

In recent years, the incidence of thrombosis diseases showed a trend of rising, which has become the first killer of human health. Although tradetional anticoagulant drugs are widely used in clinical, there are many shortcomings of these drugs, such as narrow therapeutic window, large differences of individual dosage, and easy to interact with many other drugs and food and so on. Novel anticoagulant drugs are urgently needed.Researchs have shown that a small molecule polypeptide compound has good activity to the clotting factor Xa. This kind of compound is composed of three parts:benzene sulfonyl part, methyl benzene methylamine and two amino acids. The L-shaped structure characteristic matches the structure of the target protein. The hydrophobic benzene methyl sulfonyl group binds to S1 area of factor Xa. Part of methyl benzene methylamine occupies S4 pocket of clotting factor Xa.Basis on the literatures both at home and abroad, the basic structure of the compounds that have been reported has been improved with substituents. In this paper, cyclic amino acids proline and side chain amino acids with special functional groups such as glutamic acid and glutamine are introduced in compound. In order to examine whether the introduction of this kind of amino acids affect factor Xa activity. These compounds were screened using the method of molecular docking. The results show that the structure of compound can consistent with L type structure of the target. Some compounds have inhibitory effect on blood coagulation factor Xa.These compound synthesis route were designed and the compounds were synthetized. Firstly we synthesis each fragments, and then with the DCC/HOBt as coupling agent, all the parts were connect together through peptide bond. All target compounds were validated by NMR and other detection methods.The analysis experiment were peformed with three parameters, half maximal inhibitory concentration (IC50), activated partial thromboplastin time (APTT) and prothrombin time (PT). The experimental determination results were in accordance with the docking results and verify the credibility of the molecular simulation. Results show that the compounds can prolong APTT and PT and have the activity of anticoagulant.ADMET predictions of synthetic compounds were carried using Discoery Stutio. Predicted results revealed that the synthetic compounds performed well at pharmacokinetic aspects. The rates of their plasma protein binding are less than 90%. But three compounds have potential hepatotoxicity.In a word,10 anticoagulant compounds were designed and synthetized. These compounds show certain activity after docking simulation experiment and the credibility of the activity in vitro was verified in this paper. Research result shows that the introduction of cyclic amino acid had no obvious effect on the activity, while glutamic acid especially ethyl ester of glutamic acid in P2 prominent have great influence on activity. These works would certainly be useful for the development of peptide mimetic of anticoagulant drugs.