In silico analyses of acetylcholinesterase (AChE) and its genetic variants in interaction with the anti‐Alzheimer drug Rivastigmine

Abstract

Alzheimer's disease (AD) is the leading cause of dementia worldwide. Despite causing great social and economic impact, there is currently no cure for AD. The most effective therapy to manage AD symptoms is based on acetylcholinesterase inhibitors (AChEi), from which rivastigmine presented numerous benefits. However, mutations in AChE, which affect approximately 5% of the population, can modify protein structure and function, changing the individual response to Alzheimer's treatment. In this study, we performed computer simulations of AChE wild type and variants R34Q, P135A, V333E, and H353N, identified by one or more genome‐wide association studies, to evaluate their effects on protein structure and interaction with rivastigmine. The functional effects of AChE variants were predicted using eight machine learning algorithms, while the evolutionary conservation of AChE residues was analyzed using the ConSurf server. Autodock4.2.6 was used to predict the binding modes for the hAChE–rivastigmine complex, which is still unknown. Molecular dynamics (MD) simulations were performed in triplicates for the AChE wild type and mutants using the GROMACS packages. Among the analyzed variants, P135A was classified as deleterious by all the functional prediction algorithms, in addition to occurring at highly conserved positions, which may have harmful consequences on protein function. The molecular docking results suggested that rivastigmine interacts with hAChE at the upper active‐site gorge, which was further confirmed by MD simulations. Our MD findings also suggested that the complex hAChE‐rivastigmine remains stable over time. The essential dynamics revealed flexibility alterations at the active‐site gorge upon mutations P135A, V333E, and H353N, which may lead to strong and nonintuitive consequences to hAChE binding. Nonetheless, similar binding affinities were registered in the MMPBSA analysis for the hAChE wild type and variants when complexed to rivastigmine. Finally, our findings indicated that the rivastigmine binding to hAChE is an energetically favorable process mainly driven by negatively charged amino acids.

In Silico Analyses of a Promising Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis Targeting Superoxide Dismutase I Protein

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“…SOD1 atoms were used to calculate the radius of gyration (Rg) and solvent-accessible surface area (SASA). The number of protein-ligand contacts and minimum distances between these groups were assessed using a cut-off range of 5 Å [20].…”

“…Moreover, differences in the genetic background existing in the overall population significantly influence drug efficiency, which can manifest as limited pharmacological activity [18]. Following the methodology previously established by our group [20][21][22], we investigated in silico the interactions between SOD1 wild-type and its variants A4V, and D90A with the SBL-1 compound, in addition to assessing the ADMET (absorption, distribution, metabolism, excretion, and toxicity) profile of SBL-1.…”

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Analysis on the thermal decomposition kinetics and storage period of biomass-based lycorine galanthamine

“…Considering the medical and economic burden of treating AD ( Zhang et al, 2022 ), the development of highly effective and less toxic drugs for AD has become a critical issue to be addressed. At present, there is no specific treatment for AD, and clinical treatment with acetylcholinesterase inhibitor (AChEI) drugs is commonly used ( Pereira et al, 2022 ). The natural products are an important source of AChEI, and the identification of AChEI from plants with high selectivity and low toxic side effects has been the top research area in the pharmaceutical field ( Chen et al, 2016 ), as well as being the most inspiring topic for investigating and developing drug treatment of AD.…”