Discovery of non‐oxime reactivators using an in silico pharmacophore model of reactivators for tabun‐inhibited acetylcholinesterase

Abstract

We developed a rational strategy for the discovery of non‐oxime reactivators for OP inhibited AChE, which is based on our pharmacophore model (Chem Res & Toxicol 2010, 23, 26–36) of oxime reactivators for tabun inhibited AChE. We utilized the model for virtual screening of the WRAIR‐CIS database and identified several non‐oxime reactivators in an in vitro assay with DFP‐inhibited eel AChE. The model contained a hydrogen bond acceptor and a hydrogen bond donor site at the two terminal regions, and an aromatic ring in the central region of the non‐oximes. Quantum chemically calculated stereoelectronic properties were found to be consistent with the model. The identified non‐oximes were down selected on the basis of fit score to the pharmacophore, conformational energy for the fit, favorable in silico blood brain barrier penetrability, log P, and toxicity (LOAEL and rat oral LD50), and using an in silico 3D protein‐ligand search procedure, computing binding affinities and docking the non‐oximes to the active site of the crystal structure of tabun‐inhibited AChE (PDB# 2GYU). First, compounds were evaluated, twelve were found to have moderate to weak reactivation. After refinement, compounds were tested, five showed efficacy about 10‐fold less than 2‐PAM. We are now iteratively refining the model to optimize the discovery of novel non‐oxime reactivators. (Supported by DTRA Proposal: E0057_08_WR_C).