Unraveling the Potential of Reduced Coumarins as Anticoagulating Agents via Targeting Human Coagulation Factor XA: An In Silico Approach

ABSTRACT Clotting, or coagulation is the process by which blood turns from a liquid to a gel and forms a clot. Factor Xa (FXa) is essential for thrombin production in clot formation, but excessive thrombin can cause thrombosis. Chemical scaffolds, especially coumarins have shown their potential as potent, selective FXa inhibitors with promising anticoagulant properties. This work aims to investigate the potential of reduced coumarin‐based structures as effective anticoagulants targeting FXa. Molecular docking and molecular dynamics simulations were explored to understand the interactions. Further, MM‐PBSA simulations were performed to determine the change in energy for the formation of the complex. The binding affinity from docking studies for 8‐ethyl‐4‐phenylchroman‐2‐one (CMPD227) with the 1NFY was found to be best and is −7.9 kcal/mol, and it was compared with the docking energy of 49 anticoagulant and antiplatelet drugs. RMSD and RMSF graphs were extracted from the MD simulations through GROMACS and AMBER and were compared. DFT calculation of the CMPD227 and key interacting residues has been performed. ADME analysis indicated favorable pharmacokinetic properties, including high absorption, moderate distribution, low central nervous system exposure, and controlled elimination, suggesting good oral bioavailability. Eigenvector analysis was used to highlight important atomic movements of the complex using principal component analysis, and flexible areas were found to be potential binding sites. The results of this study provide insightful information about the use of reduced coumarin‐based FXa inhibitors as promising drugs in anticoagulant therapy.