化学
药理学
药物发现
斑马鱼
胆碱酯酶
多奈哌齐
体内
药品
对接(动物)
生物信息学
疾病
痴呆
生物化学
生物
医学
内科学
生物技术
护理部
基因
作者
Bengisu Turgutalp,Prabesh Bhattarai,Tuğba Erçetin,Chiara Luise,Rengin Reıs,Enise Ece Gürdal,Andreas Isaak,Derya Biriken,Elisabeth Dinter,Hande Sipahi,Dirk Schepmann,Anna Junker,Bernhard Wünsch,Wolfgang Sippl,Hayrettin Ozan Gülcan,Çağhan Kızıl,Mine Yarım
标识
DOI:10.1021/acs.jmedchem.2c01003
摘要
Drug development efforts that focused on single targets failed to provide effective treatment for Alzheimer’s disease (AD). Therefore, we designed cholinesterase inhibition (ChEI)-based multi-target-directed ligands (MTDLs) to simultaneously target AD-related receptors. We built a library of 70 compounds, sequentially screened for ChEI, and determined σ1R, σ2R, NMDAR-GluN2B binding affinities, and P2X7R antagonistic activities. Nine fulfilled in silico drug-likeness criteria and did not display toxicity in three cell lines. Seven displayed cytoprotective activity in two stress-induced cellular models. Compared to donepezil, six showed equal/better synaptic protection in a zebrafish model of acute amyloidosis-induced synaptic degeneration. Two P2X7R antagonists alleviated the activation state of microglia in vivo. Permeability studies were performed, and four did not inhibit CYP450 3A4, 2D6, and 2C9. Therefore, four ChEI-based lead MTDLs are promising drug candidates for synaptic integrity protection and could serve as disease-modifying AD treatment. Our study also proposes zebrafish as a useful preclinical tool for drug discovery and development.
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