当前位置：
X-MOL 学术
›
J. Med. Chem.
›
论文详情
Our official English website, www.x-mol.net, welcomes your
feedback! (Note: you will need to create a separate account there.)
Discovery of Benzopyridone-Based Transient Receptor Potential Vanilloid 1 Agonists and Antagonists and the Structural Elucidation of Their Activity Shift
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-01-01 , DOI: 10.1021/acs.jmedchem.0c00982 Shivaji A. Thorat 1 , Yoonji Lee 2, 3 , Aeran Jung 1 , Jihyae Ann 1 , Songyeon Ahn 1 , Jisoo Baek 1 , Dongxu Zuo 1 , Nayeon Do 1 , Jin Ju Jeong 1 , Peter M. Blumberg 4 , Timothy E. Esch 4 , Noe A. Turcios 4 , Larry V. Pearce 4 , Hee-Jin Ha 5 , Young Dong Yoo 5 , Sunhye Hong 2 , Sun Choi 2 , Jeewoo Lee 1
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-01-01 , DOI: 10.1021/acs.jmedchem.0c00982 Shivaji A. Thorat 1 , Yoonji Lee 2, 3 , Aeran Jung 1 , Jihyae Ann 1 , Songyeon Ahn 1 , Jisoo Baek 1 , Dongxu Zuo 1 , Nayeon Do 1 , Jin Ju Jeong 1 , Peter M. Blumberg 4 , Timothy E. Esch 4 , Noe A. Turcios 4 , Larry V. Pearce 4 , Hee-Jin Ha 5 , Young Dong Yoo 5 , Sunhye Hong 2 , Sun Choi 2 , Jeewoo Lee 1
Affiliation
|
Among a series of benzopyridone-based scaffolds investigated as human transient receptor potential vanilloid 1 (TRPV1) ligands, two isomeric benzopyridone scaffolds demonstrated a consistent and distinctive functional profile in which 2-oxo-1,2-dihydroquinolin-5-yl analogues (e.g., 2) displayed high affinity and potent antagonism, whereas 1-oxo-1,2-dihydroisoquinolin-5-yl analogues (e.g., 3) showed full agonism with high potency. Our computational models provide insight into the agonist–antagonist boundary of the analogues suggesting that the Arg557 residue in the S4–S5 linker might be important for sensing the agonist binding and transmitting signals. These results provide structural insights into the TRPV1 and the protein–ligand interactions at a molecular level.
中文翻译：
基于苯并吡啶酮的瞬态受体潜在香草醛1激动剂和拮抗剂的发现及其活性转移的结构解析
在一系列作为人类瞬时受体潜在vanilloid 1（TRPV1）配体的基于苯并吡啶酮的支架中，两个异构体苯并吡啶酮的支架表现出一致而独特的功能，其中2-oxo-1,2-dihydroquinolin-5-yl类似物（例如，2）显示出高亲和力和强效拮抗作用，而1-氧-1,2-二氢异喹啉-5-基类似物（例如3）显示出具有高效力的完全激动作用。我们的计算模型提供了对类似物激动剂-拮抗剂边界的深入了解，表明S4-S5接头中的Arg557残基可能对于检测激动剂结合和传递信号很重要。这些结果在分子水平上提供了对TRPV1和蛋白质-配体相互作用的结构见解。
更新日期：2021-01-14
中文翻译：
基于苯并吡啶酮的瞬态受体潜在香草醛1激动剂和拮抗剂的发现及其活性转移的结构解析
在一系列作为人类瞬时受体潜在vanilloid 1（TRPV1）配体的基于苯并吡啶酮的支架中，两个异构体苯并吡啶酮的支架表现出一致而独特的功能，其中2-oxo-1,2-dihydroquinolin-5-yl类似物（例如，2）显示出高亲和力和强效拮抗作用，而1-氧-1,2-二氢异喹啉-5-基类似物（例如3）显示出具有高效力的完全激动作用。我们的计算模型提供了对类似物激动剂-拮抗剂边界的深入了解，表明S4-S5接头中的Arg557残基可能对于检测激动剂结合和传递信号很重要。这些结果在分子水平上提供了对TRPV1和蛋白质-配体相互作用的结构见解。
京公网安备 11010802027423号