Resumen
Alzheimer’s disease (AD) is a neurological disorder caused by the abnormal accumulation of hyperphosphorylated proteins. Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a dual phosphorylation enzyme which phosphorylates the amyloid-β (Aβ) and neurofibrillary tangles (NFTs). A high throughput virtual screening approach was applied to screen a library of 98,071 compounds against DYRK1A using different programs including AutoDock Vina, Smina, and idock. Based on the binding affinities, we selected 330 compounds for absorption, distribution, metabolism, excretion, and toxicity (ADMET) analysis. Various pharmacokinetics parameters were predicted using the admetSAR server, and based on the pharmacokinetics results, 14 compounds were selected for cross-docking analysis using AutoDock. Cross-docking analysis revealed four compounds, namely, ZINC3843365 (−11.07 kcal/mol−1), ZINC2123081 (−10.93 kcal/mol−1), ZINC5220992 (−10.63 kcal/mol−1), and ZINC68569602 (−10.35 kcal/mol−1), which had the highest negative affinity scores compared to the 10 other molecules analyzed. Density functional theory (DFT) analysis was conducted for all the four top-ranked compounds. The molecular interaction stability of these four compounds with DYRK1A has been evaluated using molecular dynamics (MD) simulations on 100 nanoseconds followed by principal component analysis (PCA) and binding free energy calculations. The Gibbs free energy landscape analysis suggested the metastable state and folding pattern of selected docking complexes. Based on the present study outcome, we propose four antagonists, viz., ZINC3843365, ZINC2123081, ZINC5220992, and ZINC68569602 as potential inhibitors against DYRK1A and to reduce the amyloid-β and neurofibrillary tangle burden. These screened molecules can be further investigated using a number of in vitro and in vivo experiments.
Idioma original | English |
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Número de artículo | 1078987 |
Publicación | Frontiers in Molecular Biosciences |
Volumen | 9 |
DOI | |
Estado | Published - ene. 19 2023 |
Nota bibliográfica
Funding Information:TS and RS acknowledge the ICMR grant, as RS was awarded the ICMR-Senior Research Fellowship during the tenure of which this study was conducted. Nikki Kelvin (The Journal of Infection in Developing Countries) provided editing assistance throughout the preparation of this manuscript.
Funding Information:
This work was supported by grants from the Canadian Institutes of Health Research, the Genome Canada/Atlantic Genome, the Research Nova Scotia, the Dalhousie Medical Research Foundation, and the Li Ka Shing Foundation. DK is Canada Research Chair in Translational Vaccinology and Inflammation.
Funding Information:
This work was supported by grants from the Canadian Institutes of Health Research, the Genome Canada/Atlantic Genome, the Research Nova Scotia, the Dalhousie Medical Research Foundation, and the Li Ka Shing Foundation. DK is Canada Research Chair in Translational Vaccinology and Inflammation.
Publisher Copyright:
Copyright © 2023 Shukla, Kumar, Kelvin and Singh.
ASJC Scopus Subject Areas
- Biochemistry
- Molecular Biology
- Biochemistry, Genetics and Molecular Biology (miscellaneous)
PubMed: MeSH publication types
- Journal Article