A computational view on the significance of E-ring in binding of (+)-arisugacin A to acetylcholinesterase

  • Bioorg Med Chem Lett. 2015 Nov 1;25(21):4848-4853. doi: 10.1016/j.bmcl.2015.06.047.
Ziyad F Al-Rashid  1 ,  Richard P Hsung  2
Affiliations
  • 1. Alchemical Research, LLC, 260 East Wall Street, Bethlehem, PA 18018, USA. Electronic address: [email protected].
  • 2. Division of Pharmaceutical Sciences, School of Pharmacy, and Department of Chemistry, University of Wisconsin, Madison, WI 53705, USA. Electronic address: [email protected].
PMID: 26159481 DOI: 10.1016/j.bmcl.2015.06.047
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.

Keywords
(+)-Arisugacin A; Acetylcholinesterase; Alzheimer’s disease; Computational modeling; E-ring conformation; E-ring substitutions; Territrems.
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