Molecular Interaction of the Antineoplastic Drug, Methotrexate with Human Brain Acetylcholinesterase: A Docking Study

Shazi Shakil, Mohammad A. Kamal, Shams Tabrez, Adel M. Abuzenadah, Adeel G.A. Chaudhary, Ghazi A. Damanhouri

Abstract

This study describes molecular interactions between human brain acetylcholinesterase (AChE) and the well known anti-neoplastic drug, methotrexate (MTX) and its comparison to ‘AChE-cyclophosphamide (CP) interactions’ that we reported previously. Docking between MTX and AChE was performed using ‘Autodock4.2’. Hydrophobic interactions and hydrogen bonds both play an equally important role in the correct positioning of MTX within the ‘acyl pocket’ as well as ‘catalytic site’ of AChE to permit docking. However, docking of CP to AChE is largely dominated by hydrophobic interactions. Such information may aid in the design of versatile AChE-inhibitors, and is expected to aid in safe clinical use of MTX. Scope still remains in the determination of the three-dimensional structure of AChE-MTX complex by X-ray crystallography to validate the described data. The current computational study supports our previous experimental study which concluded a mixed inhibition model for AChE-inhibition by MTX. Furthermore, the present report confirms that MTX is a more efficient inhibitor of human brain AChE compared to CP with reference to K_i and ΔG values.

Keywords: Methotrexate, Docking, Enzyme-Inhibition, Human Brain Acetylcholinestrase, MTX, CTX-M-15, Cephalosporin, Cefotaxime, AChE, Desolvation, Cyclophosphamide, Galantamine