DFT and molecular docking investigation of rivastigmine and pyridostigmine derivatives as AChE inhibitors and their interaction with carbon nanocages

This study investigates rivastigmine and pyridostigmine derivatives as acetylcholinesterase (AChE) inhibitors and evaluates their delivery via carbon-based fullerenes (C 20 , C 32 , and C 60 ). AChE regulates cholinergic neurotransmission by catalyzing the rapid hydrolysis of acetylcholine; consequently, the inhibition of human AChE (hAChE) remains a cornerstone therapeutic strategy for the symptomatic management of Alzheimer’s disease. Utilizing Density Functional Theory (DFT) calculations in both gas and aqueous phases, the structural stability and feasibility of these nanocages as drug delivery platforms were assessed. Among the candidates, the C 60 fullerene exhibited superior thermodynamic stability, establishing it as the most viable nanocarrier. The formation of stable drug-fullerene complexes in both environments confirms energetically favorable host-guest interactions. Frontier-orbital energy analysis revealed significant perturbations in the electronic properties of pyridostigmine derivatives upon interaction with the nanostructures, indicating enhanced chemical reactivity and delivery compatibility. Molecular docking simulations were subsequently employed to compare the binding affinities of rivastigmine and pyridostigmine within the hAChE active site, identifying optimal precursors for structural modification. The adsorption behavior of the novel derivatives, specifically R3 and P2, was then rigorously characterized. Analysis of adsorption energies, charge transfer, and HOMO-LUMO gap variations, complemented by Molecular Electrostatic Potential (MEP) and mapping Density of States (DOS), elucidated the electronic structures and reactive sites of these systems. The findings illustrate that while both derivatives exhibit inhibitory potential, C 60 provides a promising nanoplatform for delivery of the P2 derivative through non-covalent physical interactions. The work extends fullerene-based carrier design to a permanently cationic anticholinesterase and shows that cage curvature and guest charge state together determine whether adsorption proceeds by chemisorption or physisorption.