In silico and in vitro evaluation of two novel oximes (K378 and K727) in comparison to K-27 and pralidoxime against paraoxon-ethyl intoxication

Maria Arshad, Muhammad Qaiser Fatmi, Kamil Musilek, Alamdar Hussain, Kamil Kuca, Georg Petroianu, H. Kalász, Syed Muhammad Nurulain

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Organophosphate (OP) poisoning is a major global health issue; while compounds from this group have been used intensively over the last century, an effective antidote is still lacking. Oxime-type acetylcholinesterase (AChE) reactivators are used to reactivate the OP inhibited AChE. Pralidoxime is the only US Food and Drug Administration approved oxime for therapeutic use but its efficacy has been disappointing. Two novel oximes (K378 and K727) were investigated in silico and in vitro and compared with an experimental oxime (kamiloxime; K-27) and pralidoxime. In silico the molecular interactions between AChE and oximes were examined and binding energies were assessed. LogP (predicted log of the octanol/water partition coefficient) was estimated. In vitro the intrinsic ability of the oximes to inhibit AChE (IC50) and their reactivation potency (R50) when used in paraoxon inhibited human RBC-AChE was determined. Molecular docking revealed that K378 and K727 bind to the peripheral site(s) with high binding energies in contrast to the central binding of K-27 and pralidoxime. LogP values indicating that the novel compounds are significantly less hydrophilic than K-27 or pralidoxime. IC50 of K378 and K727 were comparable (0.9 and 1 µM, respectively) but orders of magnitude lower than comparators. R50 values revealed their inability to reactivate paraoxon inhibited AChE. It is concluded that the novel oximes K378 and K727 are unlikely to be clinically useful. The in silico and in vitro studies described allow avoidance of unnecessary in vivo animal work and contribute to the reduction of laboratory animal use.

Original languageEnglish
Pages (from-to)62-68
Number of pages7
JournalToxicology Mechanisms and Methods
Volume28
Issue number1
DOIs
Publication statusPublished - Jan 2 2018

Fingerprint

Oximes
Computer Simulation
Acetylcholinesterase
Paraoxon
Organophosphates
Binding energy
Inhibitory Concentration 50
Animals
Organophosphate Poisoning
Octanols
Antidotes
Molecular interactions
Laboratory Animals
Therapeutic Uses
United States Food and Drug Administration
pralidoxime
In Vitro Techniques
ethylparaoxon
Health
Water

Keywords

  • K-27
  • K378
  • K727
  • organophosphates
  • Oximes
  • paraoxon-ethyl
  • pralidoxime

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

In silico and in vitro evaluation of two novel oximes (K378 and K727) in comparison to K-27 and pralidoxime against paraoxon-ethyl intoxication. / Arshad, Maria; Fatmi, Muhammad Qaiser; Musilek, Kamil; Hussain, Alamdar; Kuca, Kamil; Petroianu, Georg; Kalász, H.; Nurulain, Syed Muhammad.

In: Toxicology Mechanisms and Methods, Vol. 28, No. 1, 02.01.2018, p. 62-68.

Research output: Contribution to journalArticle

Arshad, Maria ; Fatmi, Muhammad Qaiser ; Musilek, Kamil ; Hussain, Alamdar ; Kuca, Kamil ; Petroianu, Georg ; Kalász, H. ; Nurulain, Syed Muhammad. / In silico and in vitro evaluation of two novel oximes (K378 and K727) in comparison to K-27 and pralidoxime against paraoxon-ethyl intoxication. In: Toxicology Mechanisms and Methods. 2018 ; Vol. 28, No. 1. pp. 62-68.
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