title: A computational view on the significance of E-ring in binding of (+)-arisugacin A to acetylcholinesterase.
abstract: A computational docking study of a series of de novo structural analogs of the highly potent, non-nitrogen containing, acetylcholinesterase inhibitor (+)-arisugacin A is presented. In direct comparison to the recently reported X-ray single-crystal structure of (+)-territrem B bound hAChE, the modeling suggests that there is a unique conformational preference for the E-ring that is responsible for the superior inhibitory activity of (+)-arisugacin A against hAChE relative to (+)-territrem B, and that substitutions on the E-ring also play an important role in the protein-ligand interaction.
authors.affiliation: Alchemical Research, LLC, 260 East Wall Street, Bethlehem, PA 18018, USA. Electronic address: zalrashid@alchemicalresearch.com.
authors.forename: Ziyad F
authors.initials: ZF
authors.lastname: Al-Rashid
authors.affiliation: Division of Pharmaceutical Sciences, School of Pharmacy, and Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA. Electronic address: rhsung@wisc.edu.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Hsung
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D011714:Pyrans; C432303:arisugacin A; D000110:Acetylcholinesterase
keywords: (+)-Arisugacin A; Acetylcholinesterase; Alzheimer’s disease; Computational modeling; E-ring conformation; E-ring substitutions; Territrems