biostudies-literatureMortel SLRNHLBI NIH HHS26694-26704https://www.ebi.ac.uk/biostudies/studies/S-EPMC12224098biostudies-literatureUnknown10(25)Vitamin K epoxide reductase (VKOR) is an enzyme involved in the activation of several clotting factors, making its inhibition a well-known mechanism of anticoagulant action. Though the VKOR inhibitor warfarin remains essential and popular today, its adverse effects still make it a high-risk drug. This study intends to identify novel compounds with predicted VKOR inhibition and pharmacokinetic stability and explain the mechanistic basis of their action. A combination of pharmacophore modeling, druglikeness prediction, and molecular docking was used to find hits from existing compound libraries. The top hits showed <i>in vitro</i> activity at the micromolar level in a cell-based VKOR inhibition assay using human embryonic kidney 293 cells, led by A114 (IC<sub>50</sub> = 5.51 μM) and A116 (ICACS omega<i>In Silico</i> and <i>In Vitro</i> Studies of Potential Novel Vitamin K Epoxide Reductase (VKOR) Inhibitors Suggest an Updated Structure-Activity Relationship.PMC12224098R01 HL131690Wang MMortel SLRMacalino SJYTie JKfalse<i>In Silico</i> and <i>In Vitro</i> Studies of Potential Novel Vitamin K Epoxide Reductase (VKOR) Inhibitors Suggest an Updated Structure-Activity Relationship.Vitamin K epoxide reductase (VKOR) is an enzyme involved in the activation of several clotting factors, making its inhibition a well-known mechanism of anticoagulant action. Though the VKOR inhibitor warfarin remains essential and popular today, its adverse effects still make it a high-risk drug. This study intends to identify novel compounds with predicted VKOR inhibition and pharmacokinetic stability and explain the mechanistic basis of their action. A combination of pharmacophore modeling, druglikeness prediction, and molecular docking was used to find hits from existing compound libraries. The top hits showed <i>in vitro</i> activity at the micromolar level in a cell-based VKOR inhibition assay using human embryonic kidney 293 cells, led by A114 (IC<sub>50</sub> = 5.51 μM) and A116 (IC2025-01-01T00:00:00Z2025 Jul2026-06-02T08:44:51.162Z2026-04-16T03:12:49.797ZS-EPMC122240984062100710.1021/acsomega.5c01116