Evaluation of Apremilast as a Potential Inhibitor of Activated Factor XII: In-Vitro and In-Silico Approaches

This study aimed to evaluate the inhibitory effects of apremilast on activated coagulation factor XII (FXIIa) using chromogenic enzyme assays and to examine molecular interactions between apremilast and benzamidine with the target protein ۶I۶۳ (FXIIa) through in silico techniques including docking, structural analyses, and dynamic simulations. The interaction strength of these complexes, focusing on hydrogen bonds, Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), and Solvent Accessible Surface Area (SASA), was analyzed. Additionally, the selectivity of apremilast toward FXIIa over other related serine proteases (FIXa, FXa, FXIa, and plasma kallikrein) was determined using chromogenic assays. The findings indicated that apremilast has a significant inhibitory effect on FXIIa, while no notable effects were observed on the other proteases, suggesting selectivity for FXIIa. Furthermore, apremilast showed stronger binding affinity with ۶I۶۳ (−۶.۹ kcal/mol) compared to benzamidine (−۵.۳ kcal/mol), indicating a more stable and specific interaction. Apremilast induced greater compactness and stability of the complex, with lower RMSD and SASA values, whereas benzamidine favored a more flexible and less stable interaction. These results highlight distinct mechanisms by which each ligand interacts with FXIIa and provide insights into their therapeutic potential, suggesting apremilast could be effective in treating FXIIa-related diseases. In addition, ADME analysis revealed that benzamidine has better solubility, intestinal absorption, and excretion, while apremilast exhibits superior oral absorption and stronger inhibition of cytochrome P۴۵۰ enzymes. Toxicity studies showed both compounds are mutagenic. Taken together, apremilast could serve as a lead compound for developing new therapeutic agents targeting FXIIa-related diseases.

کلیدواژه ها:

Factor XIIa ، Apremilast ، In vitro ، In silico ، Dynamic Molecular ، SASA