Constituents of Stachys plants as potential dual inhibitors of AChE and NMDAR for the treatment of Alzheimer’s disease: a molecular docking and dynamic simulation study

Alzheimer's disease (AD) is a chronic neurodegenerative condition characterized by progressive cognitive impairment. While the formation of β-amyloid plaques and neurofibrillary tangles are the hallmarks features of AD, the downstream consequence of these byproducts is the disruption of the cholinergic and glutamatergic neural systems. Growing evidence for the existence of interplay between AChE and NMDARs has opened up new venues for the discovery of novel ligands endowed with anticholinesterase and NMDAR-blocking activity. Plants belonging to the stachys genus have been extensively explored for having a broad range of therapeutic applications and have been used traditionally for millennia, to treat various CNS-related disorders, which makes them the ideal source of novel therapeutics. The present study was designed to identify natural dual-target inhibitors for AChE and NMDAR deriving from stachys genus for their potential use in AD. Using molecular docking, drug-likeness-profiling, MD simulation and MMGBSA calculations, an in-house database of biomolecules pertaining to the stachys genus was shortlisted based on their binding affinity, overall stability and critical ADMET parameters. Pre- and post-MD analysis revealed that Isoorientin effectively binds to AChE and NMDAR with various vital interactions, exhibits a stable behavior with minor fluctuations relative to two clinical drugs used as positive control, and displays strong and consistent interactions that lasted for the majority of the simulation. Findings from this study have elucidated the rationale behind the traditional use of Stachys plants for the treatment of AD and could provide new impetus for the development of novel dual-target therapeutics for AD treatment.Communicated by Ramaswamy H. Sarma