Discovery of non-oxime reactivators using an in silico pharmacophore model of reactivators for DFP-inhibited acetylcholinesterase

Apurba K Bhattacharjee; Elizabeth Marek; Ha Thu Le; Ruthie Ratcliffe; James C DeMar; Dmitry Pervitsky; Richard K Gordon

doi:10.1016/j.ejmech.2014.11.013

Discovery of non-oxime reactivators using an in silico pharmacophore model of reactivators for DFP-inhibited acetylcholinesterase

Eur J Med Chem. 2015 Jan 27:90:209-20. doi: 10.1016/j.ejmech.2014.11.013. Epub 2014 Nov 6.

Authors

Apurba K Bhattacharjee¹, Elizabeth Marek², Ha Thu Le², Ruthie Ratcliffe², James C DeMar², Dmitry Pervitsky³, Richard K Gordon⁴

Affiliations

¹ 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.
² Department of Regulated Laboratories, Division of Regulated Activities, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
³ Division of Experimental Therapeutics, Walter Reed Army Institute of Research, Silver Spring, MD 20910, USA.
⁴ 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.

PMID: 25461321
DOI: 10.1016/j.ejmech.2014.11.013

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.

Keywords: In silico pharmacophore model; Non-oxime reactivators; OP-Inhibited AChE; Virtual screening; WRAIR-CIS database.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Acetylcholinesterase / metabolism*
Animals
Cholinesterase Inhibitors / chemistry
Cholinesterase Inhibitors / pharmacology*
Dose-Response Relationship, Drug
Drug Discovery*
Guinea Pigs
Isoflurophate / chemistry
Isoflurophate / pharmacology*
Male
Models, Molecular
Molecular Structure
Structure-Activity Relationship

Substances

Cholinesterase Inhibitors
Isoflurophate
Acetylcholinesterase