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

Publication date: Available online 16 March 2019Source: Journal of Molecular Graphics and ModellingAuthor(s): Ivan Ilin, Elena Lipets, Alexey Sulimov, Danil Kutov, Khidmet Shikhaliev, Andrey Potapov, Michael Krysin, Fedor Zubkov, Lyudmila Sapronova, Fazoyl Ataullakhanov, Vladimir SulimovAbstractFactor 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...
Source: Journal of Molecular Graphics and Modelling - Category: Molecular Biology Source Type: research