Identification of Potential Anti-Inflammatory Phytochemicals Targeting Endothelial Protein C Receptor (EPCR) Through Molecular Docking and Molecular Dynamics Simulations
TL;DR
Among the screened compounds, L114 emerged as the most promising EPCR inhibitor, suggesting that selected phytochemicals may serve as potential lead molecules for developing safer anti-inflammatory therapies targeting EPCR.
Abstract
Inflammation is a key contributor to several chronic diseases, including rheumatoid arthritis, cardiovascular disorders, and cancer. The endothelial protein C receptor (EPCR) plays a crucial role in regulating inflammation and coagulation, making it a promising therapeutic target. In this study, a structure-based computational approach was used to identify potential anti-inflammatory phytochemicals targeting EPCR. A large phytochemical library from IMPPAT and COCONUT databases was screened, followed by ADMET filtering, resulting in 278 drug-like compounds for further analysis. Molecular docking identified four lead compounds (L10, L41, L111, and L114) with stronger binding affinities than the reference drug diclofenac. These compounds formed stable interactions with key EPCR residues through hydrogen bonding, hydrophobic contacts, and π–π stacking interactions. Molecular dynamics simulations over 200 ns confirmed the structural stability of the ligand–EPCR complexes, supported by favourable RMSD, RMSF, and free-energy profiles. MM-GBSA analysis further demonstrated superior binding energies for L114 (-32.20 ± 0.02 kcal/mol), L41 (-30.15 ± 0.02 kcal/mol), and L111 (-28.19 ± 0.02 kcal/mol) compared to diclofenac (-25.18 ± 0.03 kcal/mol). Among the screened compounds, L114 emerged as the most promising EPCR inhibitor. These findings suggest that selected phytochemicals, particularly L114, may serve as potential lead molecules for developing safer anti-inflammatory therapies targeting EPCR.