Huperzine A (HupA), an alkaloid found in the club moss , has been in use for centuries in Chinese traditional medicine to treat dementia owing to its ability to inhibit the cholinergic enzyme acetylcholinesterase (AChE), thus acting as an acetylcholinesterase inhibitor (AChEI). An imbalance of metal ions in the brain is linked to Alzheimer's disease (AD) pathology. Transferrin (Tf) is a crucial player in iron homeostasis, thus highlighting its significance in AD. This study explores the plausible binding of HupA with Tf using molecular docking, molecular dynamics (MD) simulation, and free energy landscape (FEL) analyses. The docking results show that HupA binds to the functionally active region of Tf by forming three hydrogen bonds with Thr392, Glu394, and Ser688 and several hydrophobic interactions. The MD simulation analyses show that HupA binding is stable with Tf, causing minimal changes to the protein conformation. Moreover, principal component analysis (PCA) and FEL also depict the stable binding of HupA with Tf without any significant fluctuations. Further, fluorescence-based binding suggested excellent binding affinity of HupA with Tf affirming observations. Isothermal titration calorimetry (ITC) advocated the spontaneous binding of HupA with Tf. This study provides an insight into the binding mechanism of HupA with Tf, and overall, the results show that HupA, after required experimentations, can be a better therapeutic agent for treating AD while targeting Tf.
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http://dx.doi.org/10.1021/acsomega.2c03185 | DOI Listing |
Microb Cell Fact
October 2024
Molecular Microbiology Department, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
Background: Streptomyces are sporulating soil bacteria with enormous potential for secondary metabolites biosynthesis. Regulatory networks governing Streptomyces coelicolor differentiation and secondary metabolites production are complex and composed of numerous regulatory proteins ranging from specific transcriptional regulators to sigma factors. Nucleoid-associated proteins (NAPs) are also believed to contribute to regulation of gene expression.
View Article and Find Full Text PDFmSphere
May 2024
Centro de Detección Biomolecular, Benemérita Universidad Autónoma de Puebla, Puebla, Mexico.
Unlabelled: is an emerging pathogen isolated in healthcare-associated infections. A major virulence factor of this bacterium is the type VI secretion system (T6SS). The genome of harbors two T6SS gene clusters (T6SS-1 and T6SS-2), and the functional characterization of both systems showed that these two T6SSs are not expressed under the same conditions.
View Article and Find Full Text PDFNucleic Acids Res
November 2022
Molecular Microbiology Department, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland.
Bacterial chromosome topology is controlled by topoisomerases and nucleoid-associated proteins (NAPs). While topoisomerases regulate DNA supercoiling, NAPs introduce bends or coat DNA upon its binding, affecting DNA loop formation. Streptomyces, hyphal, multigenomic bacteria known for producing numerous clinically important compounds, use the highly processive topoisomerase I (TopA) to remove excessive negative DNA supercoils.
View Article and Find Full Text PDFACS Omega
November 2022
Centre of Medical and Bio-Allied Health Sciences Research, Ajman University, Ajman346, United Arab Emirates.
Huperzine A (HupA), an alkaloid found in the club moss , has been in use for centuries in Chinese traditional medicine to treat dementia owing to its ability to inhibit the cholinergic enzyme acetylcholinesterase (AChE), thus acting as an acetylcholinesterase inhibitor (AChEI). An imbalance of metal ions in the brain is linked to Alzheimer's disease (AD) pathology. Transferrin (Tf) is a crucial player in iron homeostasis, thus highlighting its significance in AD.
View Article and Find Full Text PDFJ Phys Chem B
October 2022
Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Pudong Shanghai 201203, China.
Traditional drug discovery is based on a binding affinity (thermodynamics)-driven paradigm. Numerous examples, however, demonstrated that drug efficacy does not always depend only on binding affinity but positively correlates with binding kinetics, that is, the dissociation rate constant (). Binding free energy landscape (BFEL) constructor is a computational binding kinetics prediction method, previously developed by us, that estimates the binding kinetics for ligand-protein based on their constructed binding free energy landscape, but it also reveals the detailed molecular mechanism of the binding event, hence, providing the position of transition states at the molecular level to modify/improve the binding kinetics.
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