New factor Xa inhibitors based on 1,2,3,4-tetrahydroquinoline developed by molecular modelling

Factor Xa is a serine protease representing a crucial element in the coagulation process and an attractive target for anticoagulant therapy. At the present time there are several chemical classes of factor Xa inhibitors with proven activity. Furthermore, three factor Xa inhibitors have been approved for the medical use to date. However, therapy with these medications is accompanied by substantial adverse effects. In this background, the structure-based computational approach combining molecular docking and semiempirical quantum chemical calculations was applied for a search for new effective factor Xa inhibitors. We have undertaken a few virtual screening procedures to select potential candidates for synthesis and subsequent testing. The first screen of the focused library resulted in identifying 20 compounds among which 7 compounds showed the noticeable inhibition of factor Xa at maximal concentrations, allowed by solubility. The subsequent additional screens identified 20 additional candidates. Of these, 5 substances were shown to be capable of inhibiting factor Xa at 5 μM. The best two found 1,2,3,4-tetrahydroquinoline derivatives identified by means of modelling have demonstrated IC50 values in the micromolar range. One of them turned out to be selective factor Xa inhibitor over trypsin, factors IIa, IXa and XIa. © 2019 Elsevier Inc.

Ilin I.1, 2 , Lipets E.3, 4 , Sulimov A.1, 2 , Kutov D.1, 2 , Shikhaliev K.5 , Potapov A.5 , Krysin M.5 , Zubkov F. 6 , Sapronova L. 6 , Ataullakhanov F.3, 4 , Sulimov V.1, 2
Elsevier Inc.
  • 1 Research Computer Center, Moscow State University, Leninskie Gory 1, Building 4, Moscow, 119992, Russian Federation
  • 2 Dimonta, Ltd, Nagornaya Street 15, Building 8, Moscow, 17186, Russian Federation
  • 3 Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology, 1 Samory Mashela Str., Moscow, 117997, Russian Federation
  • 4 Center for Theoretical Problems of Physicochemical Pharmacology, Russian Academy of Sciences, Kosygina Str. 4, Moscow, 119334, Russian Federation
  • 5 Voronezh State University, Universitetskaya Sq. 1, Voronezh, 394018, Russian Federation
  • 6 Department of Organic Chemistry, Peoples’ Friendship University of Russia (RUDN University), 6 Miklukho-Maklaya St., Moscow, Russian Federation
Anticoagulants; Molecular docking; PM7; Virtual screening
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