Most cited article - PubMed ID 25920949
Virtual screening, ADMET profiling, molecular docking and dynamics approaches to search for potent selective natural molecules based inhibitors against metallothionein-III to study Alzheimer's disease
INTRODUCTION: Metallothioneins (MTs) are a class of ubiquitously occurring low-molecular-weight cysteine- and metal-rich proteins containing sulfur-based metal clusters. MT-3 exhibits neuro-inhibitory activity. The possibility to enhance the expression of MT-3 or protect it from degradation is an attractive therapeutic target, because low levels of MT-3 were found in brains of Alzheimer's disease (AD) patients. OBJECTIVES: The primary objective of this study was to test an enhancement of MT-3 cellular concentration after MT-3 binding treatment, which could prevent MT-3 degradation. METHODS: MTT assay, flow-cytometry, fluorescence microscopy, quantitative real-time polymerase chain reaction, and immunodetection of MT3 were used for analysis of effect of STOCK1N-26544, STOCK1N-26929, and STOCK1N-72593 on immortalized human microglia-SV40 cell line. RESULTS: All three tested compounds enhanced concentration of MT-3 protein in cells and surprisingly also mRNA concentration. IC50 values of tested molecules exceeded about ten times the concentration that was needed for induction of MT-3 expression. The tested compound Benzothiazolone-2 enhanced apoptosis and necrosis, but it was not of severe effect. About 80% of cells were still viable. There was no serious ROS-generation and no severe decrease in mitochondria numbers or stress induced endoplasmic reticulum changes after test treatments. The selected compound showed stable hydrophobic and electrostatic interaction during MT-3 ligand interaction. CONCLUSION: Benzothiazolone-2 compounds significantly enhanced MT-3 protein and mRNA levels. The compounds can be looked upon as one of the probable lead compounds for future drug designing experiments in the treatment of Alzheimer's disease.
- Keywords
- Alzheimer's disease, flow cytometry, immunodetection, metallothionein‐3, molecular dynamics, qRT‐PCR,
- MeSH
- Alzheimer Disease metabolism MeSH
- Apoptosis drug effects MeSH
- Benzothiazoles chemistry pharmacology MeSH
- Cell Line MeSH
- Humans MeSH
- RNA, Messenger metabolism MeSH
- Metallothionein metabolism MeSH
- Microglia drug effects metabolism MeSH
- Brain drug effects metabolism MeSH
- Reactive Oxygen Species metabolism MeSH
- Cell Survival drug effects MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Names of Substances
- Benzothiazoles MeSH
- RNA, Messenger MeSH
- Metallothionein MeSH
- Reactive Oxygen Species MeSH
