毒蕈碱乙酰胆碱受体M3抑制剂的计算机辅助设计：含三氟甲基的六氢嘧啶酮/硫酮中有前途的化合物。

IF 2.8 4区医学 Q3 CHEMISTRY, MEDICINAL

Molecular Informatics Pub Date : 2023-08-01 Epub Date: 2023-08-09 DOI:10.1002/minf.202300006

Alex Nyporko, Olga Tsymbalyuk, Ivan Voiteshenko, Sergiy Starosyla, Mykola Protopopov, Volodymyr Bdzhola

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引用次数: 0

摘要

通过计算方法在含三氟甲基的六氢嘧啶酮/硫酮中发现了IC50在纳米分子范围内的新型高选择性mAChRs M3抑制剂，可以作为有效的COPD和哮喘治疗药物的原型。化合物[6-（4-乙氧基-3-甲氧基-苯基）-4-羟基-2-硫氧基-4-（三氟甲基）六氢嘧啶-5-基]-苯基甲酮（THPT-1 ⋅ 10-7 M和3.09 ⋅ 10-9 M、分别）与异丙托溴铵相比，在相同浓度下显著竞争性抑制通过mAChR3的信号传导，而对mAChR2、烟碱胆碱能和肾上腺素能受体没有显著影响。

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Computer-aided design of muscarinic acetylcholine receptor M3 inhibitors: Promising compounds among trifluoromethyl containing hexahydropyrimidinones/thiones.

The new high selective mAChRs M3 inhibitors with IC₅₀ in nanomolecular ranges, which can be the prototypes for effective COPD and asthma treatment drugs, were discovered with computational approaches among trifluoromethyl containing hexahydropyrimidinones/thiones. Compounds [6-(4-ethoxy-3-methoxy-phenyl)-4-hydroxy-2-thioxo-4-(trifluoromethyl)hexahydropyrimidin-5-yl]-phenyl-methanone (THPT-1) and 5-benzoyl-6-(3,4-dimethoxyphenyl)-4-hydroxy-4-(trifluoromethyl)hexahydropyrimidin-2-one (THPO-4) have been proved to be a highly effective (with IC₅₀ values of 1.62 ⋅ 10^-7 M and 3.09 ⋅ 10^-9 M, respectively) at the same concentrations significantly competitive inhibit the signal conduction through mAChR3 in comparison with ipratropium bromide, without significant effect on mAChR2, nicotinic cholinergic and adrenergic receptors.

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来源期刊

Molecular Informatics CHEMISTRY, MEDICINAL-MATHEMATICAL & COMPUTATIONAL BIOLOGY

CiteScore

7.30

自引率

2.80%

发文量

审稿时长

3 months

期刊介绍： Molecular Informatics is a peer-reviewed, international forum for publication of high-quality, interdisciplinary research on all molecular aspects of bio/cheminformatics and computer-assisted molecular design. Molecular Informatics succeeded QSAR & Combinatorial Science in 2010. Molecular Informatics presents methodological innovations that will lead to a deeper understanding of ligand-receptor interactions, macromolecular complexes, molecular networks, design concepts and processes that demonstrate how ideas and design concepts lead to molecules with a desired structure or function, preferably including experimental validation. The journal''s scope includes but is not limited to the fields of drug discovery and chemical biology, protein and nucleic acid engineering and design, the design of nanomolecular structures, strategies for modeling of macromolecular assemblies, molecular networks and systems, pharmaco- and chemogenomics, computer-assisted screening strategies, as well as novel technologies for the de novo design of biologically active molecules. As a unique feature Molecular Informatics publishes so-called "Methods Corner" review-type articles which feature important technological concepts and advances within the scope of the journal.