title: Discovery of non-oxime reactivators using an in silico pharmacophore model of reactivators for DFP-inhibited acetylcholinesterase.
abstract: 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.
authors.affiliation: Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; Department of Immunology and Microbiology, School of Medicine, Georgetown University Medical Center, Washington, DC 20057, USA. Electronic address: apurba1995@yahoo.com.
authors.forename: Apurba K
authors.initials: AK
authors.lastname: Bhattacharjee
authors.affiliation: Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Marek
authors.affiliation: Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Ha Thu
authors.initials: HT
authors.lastname: Le
authors.affiliation: Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Ruthie
authors.initials: R
authors.lastname: Ratcliffe
authors.affiliation: Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: DeMar
authors.affiliation: Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
authors.forename: Dmitry
authors.initials: D
authors.lastname: Pervitsky
authors.affiliation: Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA; U.S. Army Medical Research and Materiel Command, Fort Detrick, MD 21702, USA. Electronic address: richard.k.gordon.civ@mail.mil.
authors.forename: Richard K
authors.initials: RK
authors.lastname: Gordon
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D006168:Guinea Pigs; D007531:Isoflurophate / Q000737:chemistry / Q000494:pharmacology*; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D002800:Cholinesterase Inhibitors; D007531:Isoflurophate; D000110:Acetylcholinesterase
keywords: In silico pharmacophore model; Non-oxime reactivators; OP-Inhibited AChE; Virtual screening; WRAIR-CIS database