Applications of the Near Attack Conformation (NAC) approach in the search for Acetylcholinesterase reactivators

• Published in: Chemico-biological interactions 2023-09, Vol.382, p.110619, Article 110619
• Main Authors: França, Tanos Celmar Costa, Valle da Silva, Jorge Alberto, dos Santos, Marcelo Carneiro, Cavalcante, Samir Frontino de Almeida, Kuca, Kamil
• Format: Article
• Language: English
• Subjects: AChE reactivators; Near Attack Conformation (NAC); Oximes
• ISSN: 0009-2797; 1872-7786
• DOI: 10.1016/j.cbi.2023.110619

The Near Attack Conformation (NAC) approach states that the efficiency of an enzyme-catalyzed reaction depends on the prior attainment of optimal conditions for substrate atom organization and positioning for bond formation. These conditions are prerequisites for the transition state (TS) in which the involved atoms are within the van der Waals range of contact and positioned at an angle similar to that achieved after bond formation. The successful application of this approach to investigate the reactivation mechanism of acetylcholinesterase inhibited by nerve agents has contributed to a better understanding of this mechanism and demonstrated consistent corroboration with experimental data. In this article, we summarize the accomplishments achieved thus far and outline future perspectives. •The NAC defines the pre-TS conformation.•A linear correlation can be observed between reaction rates and conformer at NAC.•NAC can be applied to the reaction of HssAChE reactivation.•Theoretical NAC results show corroboration with experimental data.