当前位置： SCI文献检索 > EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > Discovery of non-oxime reactivators using an in silico pharmacophore model of oxime reactivators of OP-inhibited acetylcholinesterase.

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

Abstract：

: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 LD(50)) assessments. In vitro reactivation efficacy of the compounds was evaluated in a DFP-inhibited eel acetylcholinesterase assay.

journal_name

Eur J Med Chem

journal_title

European journal of medicinal chemistry

authors

Bhattacharjee AK,Marek E,Le HT,Gordon RK

doi

10.1016/j.ejmech.2012.01.016

subject

Has Abstract

pub_date

2012-03-01 00:00:00

pages

229-38

eissn

0223-5234

issn

1768-3254

pii

S0223-5234(12)00017-7

journal_volume

49

pub_type

杂志文章

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