Novel hits for acetylcholinesterase inhibition derived by docking-based screening on ZINC database

J Enzyme Inhib Med Chem. 2018 Dec;33(1):768-776. doi: 10.1080/14756366.2018.1458031.

Abstract

The inhibition of the enzyme acetylcholinesterase (AChE) increases the levels of the neurotransmitter acetylcholine and symptomatically improves the affected cognitive function. In the present study, we searched for novel AChE inhibitors by docking-based virtual screening of the standard lead-like set of ZINC database containing more than 6 million small molecules using GOLD software. The top 10 best-scored hits were tested in vitro for AChE affinity, neurotoxicity, GIT and BBB permeability. The main pharmacokinetic parameters like volume of distribution, free fraction in plasma, total clearance, and half-life were predicted by previously derived models. Nine of the compounds bind to the enzyme with affinities from 0.517 to 0.735 µM, eight of them are non-toxic. All hits permeate GIT and BBB and bind extensively to plasma proteins. Most of them are low-clearance compounds. In total, seven of the 10 hits are promising for further lead optimisation. These are structures with ZINC IDs: 00220177, 44455618, 66142300, 71804814, 72065926, 96007907, and 97159977.

Keywords: ITC; Neuro 2A; PAMPA; Virtual screening; molecular docking.

MeSH terms

  • Acetylcholinesterase / metabolism*
  • Animals
  • Blood-Brain Barrier / drug effects
  • Cell Line, Tumor
  • Cell Membrane Permeability / drug effects
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Databases, Factual
  • Dose-Response Relationship, Drug
  • Drug Evaluation, Preclinical
  • Humans
  • Mice
  • Molecular Docking Simulation*
  • Molecular Structure
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology*
  • Software
  • Structure-Activity Relationship

Substances

  • Cholinesterase Inhibitors
  • Small Molecule Libraries
  • Acetylcholinesterase

Grants and funding

This work was supported by the Medical Research Council, Medical University of Sofia, Bulgaria [Grant 10-S/2016] and the Bulgarian National Science Fund [Grant DN03/9/2016].