In silico studies into the therapeutic potential of organophosphorus compounds against Alzheimer's disease

Abstract

Background Alzheimer’s disease (AD) is the most prevalent form of dementia in the elderly and is characterized by a progressive decline in cognitive function. Therapeutic strategies for AD have largely been guided by the cholinergic hypothesis, which has driven the investigation of acetylcholinesterase inhibitors, including trichlorfon, as potential therapeutic agents. Objectives This study aims to propose novel organophosphorus (OP) compounds as Hss AChE inhibitors, based on the cholinergic hypothesis. Methods A diverse array of OP compounds was systematically evaluated using advanced computational approaches, along with rigorous statistical analyses. The most promising candidates were further investigated through drug-likeness assessments, binding interaction analyses, and mechanistic simulations. Results In particular, inhibitors 12 , 13 , 20 , and 28 emerged as promising candidates for the treatment of AD. However, following a detailed safety analysis, inhibitor 12 was identified as the least toxic inhibitor, exhibiting favorable interactions with the molecular target. Molecular dynamics simulations indicated that inhibitor 12 is more energetically stabilized in the Hss AChE active site than the reference compound trichlorfon. QM/MM calculations further revealed a lower energy barrier for the Hss AChE inhibition mechanism. Conclusions These findings may facilitate the development of more effective and safer therapeutic options for the treatment of AD derived from this class of compounds.