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

被引：16

作者：

Bhattacharjee, Apurba K. ^{[1
,2
]}

Marek, Elizabeth ^{[1
]}

Le, Ha Thu ^{[1
]}

Ratcliffe, Ruthie ^{[1
]}

Demar, James C. ^{[1
]}

Pervitsky, Dmitry ^{[3
]}

Gordon, Richard K. ^{[1
,4
]}

机构：

[1] Walter Reed Army Inst Res, Div Regulated Activ, Dept Regulated Labs, Silver Spring, MD 20910 USA

[2] Georgetown Univ, Med Ctr, Sch Med, Dept Immunol & Microbiol, Washington, DC 20057 USA

[3] Walter Reed Army Inst Res, Div Expt Therapeut, Silver Spring, MD 20910 USA

[4] US Army, Med Res & Mat Command, Ft Detrick, MD 21702 USA

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2015年 / 90卷

关键词：

In silico pharmacophore model; Virtual screening; WRAIR-CIS database; Non-oxime reactivators; OP-Inhibited AChE; BLOOD-BRAIN-BARRIER; BIOLOGICAL-MEMBRANES; CRYSTAL-STRUCTURES; IMPROVED DELIVERY; PRO-DRUG; TABUN; COMPLEX; DESIGN;

D O I：

10.1016/j.ejmech.2014.11.013

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Utilizing our previously reported in silico pharmacophore model for reactivation efficacy of oximes, we present here a discovery of twelve new non-oxime reactivators of diisopropylfluorophosphate (DFP)-inhibited acetylcholinesterase (AChE) obtained through virtual screening of an in-house compound database. Rate constant (kr) efficacy values of the non-oximes were found to be within ten-fold of pralidoxime (2-PAM) in an in vitro DFP inhibited eel AChE assay and one of them showed in vivo efficacy comparable to 2-PAM against brain symptoms for DFP induced neuropathology in guinea pigs. Short listing of the identified compounds were performed on the basis of in silico evaluations for favorable blood brain barrier penetrability, octanol-water partition (Clog P), toxicity (rat oral LD50) and binding affinity to the active site of the crystal structure of a OP- inhibited AChE. (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：209 / 220

页数：12

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