Discovery of non-oxime reactivators using an in silico pharmacophore model of oxime reactivators of OP-inhibited acetylcholinesterase

We earlier reported an in silico pharmacophore model for reactivation of oximes to tabun-inhibited AChE. Since DFP (diisopropylfluorophosphate) like tabun is a G-agent simulator, we utilized the model as a rational strategy to discover non-oxime reactivators of DFP-inhibited AChE in this study. The phramacophore was used for virtual screening of two commercial databases, Maybridge and ChemNavigator, to identify reactivators which lack the oxime functions. The procedure led us to identify several potent non-oxime compounds that reactivate DFP-inhibited AChE. These non-oxime reactivators contain a nucleophile group in lieu of the oxime moiety in the compound. Five of these novel non-oximes showed Kr values within ten-fold of 2-PAM in an in vitro assay. The pharmacophore model contained a hydrogen bond acceptor, a hydrogen bond donor, and an aromatic ring features distributed in a 3D space. Calculated stereoelectronic properties reported earlier with respect to the location of molecular orbitals and electrostatic potentials were consistent with the model and the newly identified compounds. Down selection of compounds after virtual screening was performed on the basis of fit score to the model, conformational energy, and in silico evaluations for favorable blood–brain barrier (BBB) penetrability, octanol-water partition (log P), and toxicity (rat oral LD50) assessments. In vitro reactivation efficacy of the compounds was evaluated in a DFP-inhibited eel acetylcholinesterase assay.

Using our earlier reported pharmacophore, we discovered five non-oxime reactivators for DFP-inhibited acetylcholinesterase (AChE) showing Kr values within ten-fold of 2-PAM through a sample virtual screening of Maybridge and ChemNavigator databases. Figure optionsDownload as PowerPoint slideHighlights
► A rational strategy for discovery of non-oxime reactivators for nerve agents presented.
► We earlier published the first in silico pharmacophore for reactivation of GA inhibited AChE.
► Using the model, present study discovers several non-oxime reactivators of DFP-inhibited AChE.
► Through virtual screening of databases and iterative modeling five non-oximes short listed.
► In vitro Kr values of these five compounds were within ten-fold of 2-PAM, none were known before.