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E.I. Sinauridze, A.N. Romanov, O.A. Kondakova, I.V. Gribkova, S.S. Surov, A.S. Gorbatenko, Y.V. Kuznetsov, A.A. Bogolyubov, V.B. Sulimov, F.I. Ataullakhanov

Search of new thrombin inhibitors is very important objective for amelioration of antithrombotic therapy. Necessity of a fast decrease of preformed thrombin activity goes on the foreground in acute situations. It is quite reasonable to use in this case an intravenous administration of direct thrombin inhibitors to block hypercoagulation development as soon as possible. Our aim was to design new thrombin inhibitors for intravenous administration. The intravenous inhibitors get directly to blood plasma, where thrombin works. Thus the bioavailability was not an issue and we were not restricted to ligands with low basicity of P1 fragments. The selection of the effective ligands for inhibition of the target enzyme is usually very laborious, long, and expensive process. Computer-aided screening using well adjusted docking program is able to shorten this stage of the study. Such a program allows calculate the free binding energy for organic ligand and active site of target protein. We used docking program SOL developed by Research Computer Center of Moscow State University and “Dimonta” Ltd. (Moscow). The scoring functions (ΔGbinding) for compounds from National Cancer Institute (NCI, USA) and Institute of Organic Chemistry RAS (IOC, Russia) data bases were calculated on the first step of this study. After that antithrombin activities were measured experimentally for the more promising compounds. So, on the first step of this work we have executed adjustment of our program SOL for thrombin inhibitor search. At that we also discovered that some compounds with isothiuro-nium group in P1 position of the ligand were sufficiently effective thrombin inhibitors. On the next stage of the study after analysis of all results obtained we generated large virtual libraries of the ligands – possible thrombin inhibitors, taking into account all discovered patterns. Overall number of compounds, studied in virtual screening experiments, was near 6000. As a result new chemical structures were proposed as thrombin inhibitors. These structures contained traditional orcin and benzenesulfonic acid residues as P2 and P3 fragments, respectively, but new fragments in P1 position of a molecule. The calcula-tions have shown that introduction of 4- aminopyridinium (4-AP), isothiuronium (IT), or 2-aminothiazolinium (2-AT) group in P1 moiety of the compound gave rise to the high inhibitory activity. According to the calculations the inhibitory effectiveness should be better also when length of the linker between P1 and P2 fragments of inhibitor molecule decreases from 5 to 1 CH2 group. Some of aforementioned new compounds were synthesized and tested for antithrombin activity in buffer system in vitro. As a result several compounds of IT and especially of 4-AP series turned out to be the most active orcin-based thrombin inhibitors (and ones of the most active low molecular weight direct thrombin in-hibitors at all) with Ki in subnanomolar range. The obtained results show that our docking approach, augmented by experimental screening of antithrombin activity, is strategy powerful enough to find new inhibitor motifs and to improve the potency of inhibitors. The new effective thrombin inhibitors were developed. These inhibitors are very promising, but further detailed studies are necessary to confirm the possibility of medical application of these new inhibi-tors. This study was executed in frame of Basic Investigation Program of Presidium of Russian Academy of Sciences “Basic Research to Medicine”, and was supported in part by grants from Russian Foundation for Basic Research (RFBR) 09-04-00357-a and 10-07-00595-a.
May 29, 2020

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