Apurba K. Bhattacharjee
Georgetown University, USA
Title: Discovery of novel reactivators for DFP-inhibited acetylcholinesterase using in silico pharmacophore modeling
Biography
Biography: Apurba K. Bhattacharjee
Abstract
Organophosphorus (OP) compounds such as tabun, soman, DFP, sarin, cyclosarin and some pesticides are highly toxic group of compounds. Of the OP-agents, tabun (GA) is the most toxic and developing antidotes for it is a challenging problem. However, tabun being a G –simulator, less toxic DFP is frequently used in experiments for discovery of new reactivators. Using in silico strategy from our previously reported pharmacophore model containing a hydrogen bond acceptor, a hydrogen bond donor, and an aromatic ring (Chem Res & Toxicol, 2010, 23, 26-36), we discovered 17 non-oxime reactivators for DFP-inhibited AChE from a virtual screening of in-house database and two commercial databases, Maybridge and ChemNavigator. All these non-oximes contained a nucleophile group in lieu of the oxime moiety and none was reported before to have potent reactivation efficacy. Efficacy (kr) of all the 17 non-oximes were found to be within 10-fold of 2-PAM in an eel DFP-inhibited AChE in vitro assay. One the non-oximes showed in vivo efficacy comparable to 2-PAM against brain symptoms for DFP-induced neuropathology in guinea pigs. Moreover, two of them showed promising results with no major differences in brain restoration of AChE activity compared to 2-PAM after DFP exposure. Since a serious loss of cholinergic function in the central nervous system contributes significantly to the cognitive symptoms associated with AD and other advanced age related brain diseases, these results on competitive OP-inhibited AChE reactivation and inhibition behavior of non-oximes may be useful for further neurological therapeutics studies.