title: Molecular interaction of the antineoplastic drug, methotrexate with human brain acetylcholinesterase: a docking study.
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.
authors.affiliation: King Fahd Medical Research Center, King Abdulaziz University, P.O. Box 80216, Jeddah 21589, Saudi Arabia. shazibiotech@gmail.com
authors.forename: Shazi
authors.initials: S
authors.lastname: Shakil
authors.forename: Mohammad A
authors.initials: MA
authors.lastname: Kamal
authors.forename: Shams
authors.initials: S
authors.lastname: Tabrez
authors.forename: Adel M
authors.initials: AM
authors.lastname: Abuzenadah
authors.forename: Adeel G A
authors.initials: AG
authors.lastname: Chaudhary
authors.forename: Ghazi A
authors.initials: GA
authors.lastname: Damanhouri
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry*; D000970:Antineoplastic Agents / Q000737:chemistry*; D001665:Binding Sites; D001921:Brain / Q000201:enzymology; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D008727:Methotrexate / Q000737:chemistry*; D008958:Models, Molecular; D054730:Protein Interaction Domains and Motifs; D040681:Structural Homology, Protein
chemical_list: D000970:Antineoplastic Agents; D000110:Acetylcholinesterase; D008727:Methotrexate