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Interaction of Human Brain Acetylcholinesterase with Cyclophosphamide: A Molecular Modeling and Docking Study

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This study describes the interaction between human acetylcholinesterase (AChE), a key regulator of central and peripheral cholinergic function, and the widely used nitrogen mustard alkylating agent, cyclophosphamide (CP). Modeling of the AChE sequence (NCBI Accession No: AAI05061.1) was performed using ‘Swiss Model Workspace’. The protein-model was submitted to the Protein Model Database and was assigned accession number PM0077393. A plot showing normalized QMEAN scores versus protein size was made to compare the model with a non-redundant set of Protein Data Bank structures, which gave a Z-score QMEAN as -0.58. The predicted local error for the modeled structure was found to be well within tolerable limits. Z-score values for Cβ interaction, all atom interaction, solvation and torsion were found to be -1.10, -0.90, -0.06 and -0.40, respectively. Docking between CP and AChE was performed using ‘Autodock4.2’. Apart from other interaction-types, six carbon atoms of CP (C1, C2, C3, C4, C6 and C7) were determined to be involved in hydrophobic interactions with amino acid residues Y121, W233, L323, F331, F335 and Y338 of the ‘acyl pocket’ within AChE. Five carbon atoms of CP (C2, C4, C5, C6 and C7) were involved in hydrophobic interactions with 3 amino acid residues within the enzyme's ‘catalytic site’. In conclusion, hydrophobic interactions play a major role in the appropriate positioning of CP within the ‘acyl pocket’ as well as ‘catalytic site’ of AChE to permit suitable orientation and allow docking. This information may aid the design of more potent and versatile AChE-inhibitors as pharmacologic tools and drugs to characterize and treat neurological disorders, and additionally provides a model whose value can be quantitatively assessed by X-ray crystallographic analysis of the AChECP three-dimensional structure.

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Keywords: AChE; Alzheimers disease; Cyclophosphamide; DFIRE; Donepezil; Galantamine; Human Brain acetylcholinesterase; Hydrophobic interactions; Modeling; Rivastigmine; Torpedo Californica; docking; enzyme inhibition

Document Type: Research Article

Publication date: 2011-11-01

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  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
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