Nicotinonitriles, nicotinamides and their partially saturated analogs represent a promising class of heterocyclic compounds with an interesting range of biological activities. One of the most accessible and efficient approaches to the synthesis of functionalized nicotinamides is based on the reaction of active methylene malonamides with 1,3- dielectrophiles. Synthesized compounds were subjected to virtual screening using GalaxySagittarius and SwissTargetPrediction services which led to the discovery of FXIa inhibition activity in one of the compounds. In order to validate the result of virtual screening pharmacophore analysis was produced with Molecular Operating Environment software. Moreover, structural approach well known as molecular docking and the most promising method in silico was used with Molegro Virtual Docker. As a target for docking was chosen FXIa (7MBO) in a complex with milvexian. After proper protein preparing interaction of a ligand and a biotarget was evaluated with scoring-functions MolDockScore and HBond. According to ADMET data obtained after virtual assessment the hit-compound is supposed to be soluble, well absorbed in gastrointestinal tract and non-carcinogenic. The results of in silico studies allow to represent the ligand as a perspective platform for further FXIa high-selective inhibitor development.
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A New View on FXIa Potent Inhibitors: Virtual Screening, Pharmacophore Analysis and Molecular Docking of 2’-Amino-5’-Carbamoyl-3’-Cyano-2-Oxo-3’H-Spiro[indoline-3,4’-pyridine]-2-Thiolate Derivate
Published: 01 November 2023 by MDPI in 9th International Electronic Conference on Medicinal Chemistry session New Small molecules as drug candidates
https://doi.org/10.3390/ECMC2023-15620 (registering DOI)
Keywords: molecular docking, blood coagulation factors inhibitors, anticoagulants, thrombosis, pharmacophore analysis, virtual screening, drug design