Mechanistic studies of new oximes reactivators of human butyryl cholinesterase inhibited by cyclosarin and sarin

Abstract

Butyryl cholinesterase (BChE) has been seen as a key enzyme in the search for new strategies in the treatment of poisoning by organophosphates (OPs), since human BChE (HssBChE), complexed with the appropriate oxime, can be a suitable scavenger and deactivator for OPs in the blood stream. However, the efficacy of HssBChE is limited by its strict stoichiometric scavenging, slow reactivation, and propensity for aging. The improvement of the reactivation rate by new and more efficient oximes could contribute to mitigate this problem and increase the HssBChE efficiency as scavenger. Several oximes have been synthesized and tested with this goal, some with promising results, but the mechanistic aspects of the reactivation reaction are not fully understood yet. In order to better investigate this mechanism, docking and mixed quantum and molecular mechanics combined with principal components analysis were performed here to evaluate the capacity of reactivation and determine the preferred route for the reactivation reaction of two new oximes on HssBChE inhibited by the neurotoxic agents cyclosarin and sarin. Plots of potential energies were calculated and all the transition states of the reactional mechanism were determined. Our results showed a good correlation with experimental data and pointed to the most efficient oxime with both OPs. The protocol used could be a suitable tool for a preliminary evaluation of the HssBChE reactivation rates by new oximes.

Naja mossambica mossambica Cobra Cardiotoxin Targets Mitochondria to Disrupt Mitochondrial Membrane Structure and Function

“…A way to overcome this limitation is to generate multiple structures (conformations) of the protein using various softwares (e.g., Confab, OMEGA, and PC Spartan Pro). While it would be preferable to probe the conformational profile of ligands in the enzyme active site to significantly improve the accuracy of docking studies [37,38], we employed the highest level of flexibility allowed by AutoDock by using the exhaustiveness level 16, and performed three docking simulations for each ligand for statistical purposes. Hence, running docking studies using the aforementioned paramaters can add more rigor and accuracy to our docking studies and can partially account for the flexibility and conformational changes that lipids can undergo (~dozens of nanoseconds).…”

Co-immobilised 7α- and 7β-HSDH as recyclable biocatalyst: high-performance production of TUDCA from waste chicken bile

“…The docking results were selected by means of the principal components analysis and submitted to QM calculations. 33 …”

Zingiber officinale: Ayurvedic Uses of the Plant and In Silico Binding Studies of Selected Phytochemicals With Mpro of SARS-CoV-2

“…33 Molegro Virtual Docker is able to predict the most likely conformation of a ligand's binding to a macromolecule and has also been used for molecular docking studies with human butyryl cholinesterase. 34 Binding studies were carried out through blind molecular docking using AutoDock Vina. 35 Blind molecular docking enables the researcher to search throughout the entire surface of the macromolecule for binding sites of the experimental ligands.…”