Molecular modeling studies on the interactions of 7-methoxytacrine-4-pyridinealdoxime, 4-PA, 2-PAM, and obidoxime with VX-inhibited human acetylcholinesterase: a near attack conformation approach

J Enzyme Inhib Med Chem. 2019 Dec;34(1):1018-1029. doi: 10.1080/14756366.2019.1609953.

Abstract

7-methoxytacrine-4-pyridinealdoxime (7-MEOTA-4-PA, named hybrid 5C) is a compound formerly synthesized and evaluated in vitro, together with 4-pyridine aldoxime (4-PA) and commercial reactivators of acetylcholinesterase (AChE). This compound was designed with the purpose of being a prophylactic reactivator, capable of interacting with different subdomains of the active site of AChE. To investigate these interactions, theoretical results from docking were first compared with experimental data of hybrid 5C, 4-PA, and two commercial oximes, on the reactivation of human AChE (HssAChE) inhibited by VX. Then, further docking studies, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, were carried out to investigate reactivation performances, considering the near attack conformation (NAC) approach, prior to the nucleophilic substitution mechanism. Our results helped to elucidate the interactions of such molecules with the different subdomains of the active site of HssAChE. Additionally, NAC poses of each oxime were suggested for further theoretical studies on the reactivation reaction.

Keywords: 7-MEOTA-4-PA; Acetylcholinesterase; NAC; VX; molecular modeling.

MeSH terms

  • Acetylcholinesterase / metabolism
  • Cholinesterase Inhibitors / chemical synthesis
  • Cholinesterase Inhibitors / chemistry
  • Cholinesterase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Obidoxime Chloride / chemistry
  • Obidoxime Chloride / pharmacology*
  • Organothiophosphorus Compounds / chemistry
  • Organothiophosphorus Compounds / pharmacology*
  • Oximes / chemistry
  • Oximes / pharmacology*
  • Pralidoxime Compounds / chemistry
  • Pralidoxime Compounds / pharmacology*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Structure-Activity Relationship

Substances

  • 7-methoxytacrine-4-pyridinealdoxime
  • Cholinesterase Inhibitors
  • Organothiophosphorus Compounds
  • Oximes
  • Pralidoxime Compounds
  • Pyridines
  • Obidoxime Chloride
  • pyridine-4-aldoxime
  • VX
  • Acetylcholinesterase
  • pralidoxime

Grants and funding

The authors wish to thank the Military Institute of Engineering and the University of Hradec Kralové for the infrastructure, and the Brazilian financial agencies CNPq (Grant no 308225/2018–0), FAPERJ (Grant no E-02/202.961/2017), for financial support. This work was also supported by the Excellence project UHK.