A New Role for the Nonpathogenic Nonsynonymous Single-Nucleotide Polymorphisms of Acetylcholinesterase in the Treatment of Alzheimer's Disease: A Computational Study

Abstract

Single-nucleotide polymorphisms (SNPs) are implicated in the complexity of understanding the genetics of diseases and their therapeutics. Here we have attempted to determine the impact of nonsynonymous SNPs (nsSNPs) on structure, dynamics, and ligand-binding properties of the human acetylcholinesterase (hAChE) protein, which has been targeted in the treatment of Alzheimer's disease. Of the reported 153 SNPs, 4 nsSNPs, namely, A415G, P104A, V302E, and Y119H, were prioritized to be functionally unfavorable by SIFT and PolyPhen algorithms. Molecular dynamics simulation revealed these nsSNP forms to be structurally stable, and they are also considered functionally active as they lie away from the catalytic triad. However, the aromatic amino acids lining the active-site gorge exhibited altered degrees of side chain dihedral angles. Such conformational alterations were evaluated for their ability to interfere with binding of hAChE inhibitors. The inhibitors (donepezil, galantamine, rivastigmine, and tacrine) were oriented differently in comparison to the native because of the steric hindrance offered by the altered dihedral angles. Interestingly, huperzine A alone exhibited higher efficiency in its binding to the AChE and retained similar orientation irrespective of the polymorphisms since the orientation of Asp74 involved in its binding and trafficking remained unaltered in all protein forms. Therefore, we conclude that nsSNPs confer changes to the dynamicity of proteins, which in turn affects their ligand-binding properties rather than their stability. Considering the diverse polymorphic nature of hAChE, while contemplating any structure-based drug design, the common, nonpathogenic nsSNPs should be considered for the utmost efficacy of drugs.

Kinetics of acetylcholinesterase inhibition by hemp seed protein‐derived peptides

“…Hence the HPH peptides could bind to the active site to interfere with substrate binding ability to the ee AChE. At the same time, the HPH peptides have the capacity to bind to non‐active sites on the ee AChE protein, which could have led to changes in molecular conformation that distorts the active site molecular arrangement and thus there is reduced substrate binding ability (Saravanaraman et al, ; Sharma, ; Singh et al, ). The results are consistent with a recent report by Zhao et al () who showed that lysine (free amino acid) inhibited ee AChE activity through a mixed‐type mechanism.…”

“…This abberant brain and neurotransmission condition leads to Alzheimer's disease (AD) pathogenesis (Li et al, 2015;Willcox, Scapagnini, & Willcox, 2014) that contributes to increased global morbidity/mortality rate (US Burden of Disease Collaborators, 2013). The high catalytic efficiency (CE) of AChE and the importance of its inhibition in AD management has been an important research focus in the development of various therapeutic agents (Acharya, Dutta, Chaudhury, & De, 2018;Li et al, 2015;Olarewaju et al, 2018;Saravanaraman, Chinnadurai, & Boopathy, 2014;Taslimi & Gulçin, 2018;Yadav & Appukuttan, 2019;Yatesa et al, 2019;Zare-Zardini, Tolueinia, Hashemi, Ebrahimi, & Fesahat, 2013). Several synthetic AChE-inhibitory drugs have been developed for use against neurodegenerative diseases, such as dementia and AD; however, these drugs are associated with severe negative side effects (Ghribia, Ghouilaa, Omrib, Besbesb, & Janneta, 2014;Iannello et al, 2014;Kumar & Chowdhury, 2014).…”

Strategies for Continued Successful Treatment in Patients with Alzheimer’s Disease: An Overview of Switching Between Pharmacological Agents

“…Of the reported 153 SNPs, four non-specific SNPs (A415G, P104A, V302E, and Y119H) that were predicted to be functionally unfavorable were found to be structurally stable. However, their conformational alterations were found to interfere with the binding of AChE inhibitors, suggesting it to be a reason for the differential effect of ChEIs in patients with AD [ 78 ]. Similar results were observed in another study conducted in patients with AD who underwent treatment with AChE inhibitors (N=158).…”

Direct ab‐initio molecular dynamics study on the radiation effects on catalytic triad composed of Ser‐His‐Glu residues

“…On the other hand, the studying of radiation enzyme damages is limited . Acetylcholinesterase (AChE) is one of the enzymes which is composed of catalytic triad in the active site consisting of the amino acids, serine (Ser), histidine (His), and glutamic acid (Glu) . AChE can synthesize neurotransmitter acetylcholine (ACh) by the transition of acetyl groups of acetyl CoA .…”

“…[4][5][6][7] Acetylcholinesterase (AChE) is one of the enzymes which is composed of catalytic triad in the active site consisting of the amino acids, serine (Ser), histidine (His), and glutamic acid (Glu). [10][11][12] AChE can synthesize neurotransmitter acetylcholine (ACh) by the transition of acetyl groups of acetyl CoA. [13][14][15] The reaction efficiency of AChE is significantly larger than the other enzymes.…”