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In Silico Pharmacophore Modeling on Known Pyridinium Oxime Reactivators of Cyclosarin (GF) Inhibited AChE to Aid Discovery of Potential, More Efficacious Novel Non-Oxime Reactivators

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Cyclohexyl methylphosphonofluoridate (cyclosarin, cyclosin, GF) is a highly toxic organophosphorus (OP) nerve agent considered as potential warfare threats and known to be resistant to conventional oxime antidotal therapy. To aid discovery of novel antidotes for GF toxicity, a three-dimensional in silico pharmacophore model for reactivation efficacy against GF intoxication is presented. The model was generated from published experimental percentage reactivation data on oximes as changes of AChE/BuChE activities in the whole blood after cyclosarin intoxication and administration. The generated pharmacophore model was found to contain a hydrogen bond donor site and two ring aromatic sites as necessary optimal features for reactivation of GF intoxication. Stereo-electronic features of oximes reported by us earlier provided guidance to develop the model and were found to be consistent with the reported structure activity data. Furthermore, from virtual screening of two commercial databases, Maybridge and ChemNavigator using map-fitting of the model led us to identify two new non-oxime compounds showing reactivation efficacy within 10-fold range of 2-PAM for DFP-inhibited AChE. Since GF is a G simulator like DFP (diisopropylfluorophosphate), the model should have the potential for discovery of novel reactivators against GF intoxication.
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Keywords: 3D pharmacophore model; acetylcholinesterase (AChE); butyrylcholinesterase BuChE); cyclosarin (GF); in vitro; oximes; reactivation

Document Type: Research Article

Publication date: September 1, 2013

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  • Current Computer-Aided Drug Design aims to publish all the latest developments in drug design based on computational techniques. The field of computer-aided drug design has had extensive impact in the area of drug design. Current Computer-Aided Drug Design is an essential journal for all medicinal chemists who wish to be kept informed and up-to-date with all the latest and important developments in computer-aided methodologies and their applications in drug discovery. Each issue contains a series of timely, in-depth reviews written by leaders in the field, covering a range of computational techniques for drug design, screening, ADME studies, etc., providing excellent rationales for drug development.
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