Document Detail

Discovery of non-oxime reactivators using an in silico pharmacophore model of oxime reactivators of OP-inhibited acetylcholinesterase.
MedLine Citation:
PMID:  22309910     Owner:  NLM     Status:  Publisher    
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.
Apurba K Bhattacharjee; Elizabeth Marek; Ha Thu Le; Richard K Gordon
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-1-21
Journal Detail:
Title:  European journal of medicinal chemistry     Volume:  -     ISSN:  1768-3254     ISO Abbreviation:  -     Publication Date:  2012 Jan 
Date Detail:
Created Date:  2012-2-7     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0420510     Medline TA:  Eur J Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012. Published by Elsevier Masson SAS.
Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research (WRAIR), 503 Robert Grant Avenue, Silver Spring, MD 20910, USA.
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