New insights into the interaction between mammalian butyrylcholinesterase and amitriptyline: a combined experimental and computational approach

Abstract

Abstract Background Today, there is a growing recognition in the scientific community of the many roles of butyrylcholinesterase (BChE) in both physiological and pathological contexts. Objective Here, we aim at providing an accurate and comprehensive understanding of the mechanistic and structural aspects of mammalian BChE inhibition by the tricyclic antidepressant amitriptyline (AMI). Materials and methods The present work involves enzyme kinetic studies as well as protein–ligand docking and interaction profiling studies. Results We verify that AMI acts as an effective, mixed-type inhibitor of mammalian BChE, with an IC50 value of 10 μM and a Ki value of 2.25 μM. We also provide evidence showing that AMI penetrates deep into the active-site gorge of BChE where it interacts noncovalently with both the choline-binding and catalytic residues. Conclusion These findings could facilitate the prevention of the adverse metabolic sequelae of acquired BChE deficiency and also the design of new reversible anticholinesterase drugs.