Crystallography-guided discovery of carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators: insights into different protein behaviors with “short” and “long” inverse agonists was written by Yu, Ming-cheng;Yang, Feng;Ding, Xiao-yu;Sun, Nan-nan;Jiang, Zheng-yuan;Huang, Ya-fei;Yan, Yu-rong;Zhu, Chen;Xie, Qiong;Chen, Zhi-feng;Guo, Si-qi;Jiang, Hua-liang;Chen, Kai-xian;Luo, Cheng;Luo, Xiao-min;Chen, Shi-jie;Wang, Yong-hui. And the article was included in Acta Pharmacologica Sinica in 2021.Name: 1-(4-Hydroxypiperidin-1-yl)ethanone This article mentions the following:
A series of 6-substituted carbazole-based retinoic acid-related orphan receptor gamma-t (RORγt) modulators were discovered through 6-position modification guided by insights from the crystallog. profiles of the “short” inverse agonist 6. With the increase in the size of the 6-position substituents, the “short” inverse agonist 6 first reversed its function to agonists and then to “long” inverse agonists. The cocrystal structures of RORγt complexed with the representative “short” inverse agonist 6 (PDB: 6LOB), the agonist 7d (PDB: 6LOA) and the “long” inverse agonist 7h (PDB: 6LO9) were revealed by X-ray anal. However, minor differences were found in the binding modes of “short” inverse agonist 6 and “long” inverse agonist 7h. To further reveal the mol. mechanisms of different RORγt inverse agonists, we performed mol. dynamics simulations and found that “short” or “long” inverse agonists led to different behaviors of helixes H11, H11′, and H12 of RORγt. The “short” inverse agonist 6 destabilizes H11′ and dislocates H12, while the “long” inverse agonist 7h separates H11 and unwinds H12. The results indicate that the two types of inverse agonists may behave differently in downstream signaling, which may help identify novel inverse agonists with different regulatory mechanisms. In the experiment, the researchers used many compounds, for example, 1-(4-Hydroxypiperidin-1-yl)ethanone (cas: 4045-22-1Name: 1-(4-Hydroxypiperidin-1-yl)ethanone).
1-(4-Hydroxypiperidin-1-yl)ethanone (cas: 4045-22-1) belongs to piperidine derivatives. The piperidine structural motif is present in numerous natural alkaloids. These include piperine, which gives black pepper its spicy taste. Fluorinated piperidines are also the subject of continued interest in medicinal chemistry, for example in the synthesis of selective dipeptidyl peptidase II (DPP II) inhibitors. Piperidine derivatives are also used in solid-phase peptide synthesis (SPPS) and many degradation reactions.Name: 1-(4-Hydroxypiperidin-1-yl)ethanone
Referemce:
Piperidine – Wikipedia,
Piperidine | C5H11N – PubChem