The translocator protein ligands as mitochondrial functional modulators for the potential anti-Alzheimer agents

Autor: Mohammad Morshed, Sang Min Lim, Jiyoun Lee, TaeHun Kim, Jae Y Lee, Ha E Lee, Ae N Pae, Suengmok Cho, Sung J Cho, Ashwini M. Londhe, Ji W Lim, Hayoung Hwang
Rok vydání: 2021
Předmět:
Cell Survival
Drug Evaluation
Preclinical
RM1-950
Ligands
01 natural sciences
Protein Aggregation
Pathological
Small Molecule Libraries
Mice
Transcriptional Regulator ERG
Alzheimer Disease
Drug Discovery
Translocator protein
medicine
Animals
Humans
Viability assay
function modulators
translocator protein ligand
Cells
Cultured
Pharmacology
Virtual screening
Amyloid beta-Peptides
biology
Molecular Structure
010405 organic chemistry
Chemistry
Biological activity
General Medicine
medicine.disease
Small molecule
0104 chemical sciences
Cell biology
Mitochondria
010404 medicinal & biomolecular chemistry
Mitochondrial toxicity
Disease Models
Animal
Neuroprotective Agents
Mitochondrial permeability transition pore
biology.protein
Therapeutics. Pharmacology
Pharmacophore
Alzheimer’s disease
Research Article
Research Paper
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry
article-version (VoR) Version of Record
Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 831-846 (2021)
DOI: 10.6084/m9.figshare.14267582
Popis: Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34) as a TSPO ligand. After validating its biological activity against amyloid-β (Aβ) induced mitochondrial dysfunction and in acute and transgenic Alzheimer’s disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Aβ-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.
Databáze: OpenAIRE
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