期刊
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
卷 90, 期 -, 页码 209-220出版社
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
DOI: 10.1016/j.ejmech.2014.11.013
关键词
In silico pharmacophore model; Virtual screening; WRAIR-CIS database; Non-oxime reactivators; OP-Inhibited AChE
资金
- Defense Threat Reduction Agency (DTRA) [1E0057_08_WR_C]
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.
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