Atomistic Origins of Resurrection of Aged Acetylcholinesterase by Quinone Methide Precursors.

Leonardo V F Ferreira, Taináh M R Santos, Camila A Tavares, Hassan Rasouli, Teodorico C Ramalho

Abstract read

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Article in Molecules (Basel, Switzerland), 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

5 authors.

Leonardo V F FerreiraLaboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras, P.O. Box 3037, Lavras 37200-000, MG, Brazil.

Taináh M R SantosLaboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras, P.O. Box 3037, Lavras 37200-000, MG, Brazil.

Camila A TavaresLaboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras, P.O. Box 3037, Lavras 37200-000, MG, Brazil.ORCID 0000-0002-0710-3956

Hassan RasouliCenter for Basic and Applied Research, Faculty of Informatics and Management, University of Hradec Kralove, 500 03 Hradec Kralove, Czech Republic.ORCID 0000-0002-1269-1617

Teodorico C RamalhoLaboratory of Computational Chemistry, Department of Chemistry, Federal University of Lavras, P.O. Box 3037, Lavras 37200-000, MG, Brazil.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

Abstract

Nerve agents are organophosphates (OPs) that act as potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of acetylcholine. After inhibition, a dealkylation reaction of the phosphorylated serine, known as the aging of AChE, can occur. When aged, reactivators of OP-inhibited AChE are no longer effective. Therefore, the realkylation of aged AChE may offer a pathway to reverse AChE aging. In this study, molecular modeling was conducted to propose new ligands as realkylators of aged AChE. We applied a methodology involving docking and quantum mechanics/molecular mechanics (QM/MM) calculations to evaluate the resurrection kinetic constants and ligand interactions with OP-aged AChE, comparing them to data found in the literature. The results obtained confirm that this method is suitable for predicting kinetic and thermodynamic parameters of ligands, which can be useful in the design and selection of new and more effective ligands for AChE realkylation.

Indexed as

AcetylcholinesteraseCholinesterase InhibitorsIndolequinonesHumansKineticsLigandsModels, MolecularMolecular Docking SimulationMolecular Dynamics SimulationThermodynamicsAcetylcholinesteraseCholinesterase InhibitorsIndolequinonesLigandsquinone methideacetylcholinesterasemechanistic studiesnerve agentsrealkylationresurrection

Identifiers

PMID39125089

DOI10.3390/molecules29153684

PMCPMC11314168

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.