title: 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.
abstract: 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.
authors.affiliation: Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army, Institute of Research, 503 Robert Grant Avenue, Silver Spring, MD 20910, USA. apurba1995@yahoo.com
authors.forename: Apurba K
authors.initials: AK
authors.lastname: Bhattacharjee
authors.forename: Kamil
authors.initials: K
authors.lastname: Musilek
authors.forename: Kamil
authors.initials: K
authors.lastname: Kuca
mesh_terms: D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D003198:Computer Simulation; D017076:Computer-Aided Design; D015195:Drug Design; D006801:Humans; D009943:Organophosphorus Compounds / Q000037:antagonists & inhibitors*; D010091:Oximes / Q000737:chemistry* / Q000494:pharmacology*; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D002800:Cholinesterase Inhibitors; D009943:Organophosphorus Compounds; D010091:Oximes; D011726:Pyridinium Compounds; C053914:cyclohexyl methylphosphonofluoridate