Computational Cosolvent Mapping Analysis Leads to Identify Salicylic Acid Analogs as Weak Inhibitors of ST2 and IL33 Binding.
Computational Cosolvent Mapping Analysis Leads to Identify Salicylic Acid Analogs as Weak Inhibitors of ST2 and IL33 Binding.
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DOI：
10.1021/acs.jpcb.2c00341
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发表时间：
2022-03-31
影响因子：
3.3
通讯作者：
Yang, Chao-Yie
中科院分区：
文献类型：
--
作者：
Yuan, Xinrui;Chinnaswamy, Krishnapriya;Stuckey, Jeanne A.;Yang, Chao-Yie
细胞因子信号是由细胞因子受体与细胞因子结合而引发的，在免疫调节和疾病中起着重要作用。在结构上，细胞因子受体与细胞因子通过一个广泛的、坚固的界面相互作用，这是抑制剂开发的一个挑战。我们之前的计算分析表明，模拟酸性残基的丁酸优先结合ST2中与ST2内源性细胞因子IL33的酸性残基相互作用的位点（刺激-2）。为了研究小分子中的带电基团是否促进了配体与ST2的结合，我们开发了一种生化均匀时间分辨荧光法，以确定含有芳香环和带电基团的五种分子对ST2/IL33结合的抑制作用。三种分子，包括烟酸、水杨酸和苄脒，在毫摩尔浓度下表现出抑制活性。我们进一步采用计算共溶剂定位分析来确定烟酸、水杨酸和ST2之间的共同相互作用模式。通过四种具有相似或改进活性的类似化合物进一步证实了这种相互作用模式。我们的研究提供了水杨酸及其类似物抑制ST2和IL33结合的证据。结果表明，水杨酸的生物活性可能通过调节细胞外细胞因子受体和细胞因子相互作用来部分介导。
Cytokine signaling initiated by the binding of the cytokine receptors to cytokines plays important roles in immune regulation and diseases. Structurally, cytokine receptors interact with cytokines via an extensive, rugged interface that represents a challenge in inhibitor development. Our computational analysis has previously indicated that butyric acid, mimicking acidic residues, preferentially binds to sites in ST2 (Stimulation-2) that interact with acidic residues of IL33, the endogenous cytokine for ST2. To investigate if a charged group in small molecules facilitates ligand binding to ST2, we developed a biochemical homogeneous time resolved fluorescence assay to determine the inhibition of ST2/IL33 binding by five molecules containing an aromatic ring and a charged group. Three molecules, including niacin, salicylic acid, and benzamidine, exhibit inhibition activities at millimolar concentrations. We further employed the computational cosolvent mapping analysis to identify a shared mode of interaction between niacin, salicylic acid, and ST2. The mode of interaction was further confirmed by four analogous compounds that exhibited similar or improved activities. Our study provided the evidence of inhibition of ST2 and IL33 binding by salicylic acid and analogs. The results suggest that biological activity of salicylic acid may be partly mediated through modulating extracellular cytokine receptors and cytokine interaction.
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影响因子：
21.8
作者：
Cao Q;Shin WS;Chan H;Vuong CK;Dubois B;Li B;Murray KA;Sawaya MR;Feigon J;Black DL;Eisenberg DS;Jiang L
通讯作者：
Jiang L
Interleukin-1家族：回到未来。
影响因子：
32.4
作者：
Garlanda C;Dinarello CA;Mantovani A
通讯作者：
Mantovani A
影响因子：
2.6
作者：
Boga, Salih;Alkim, Huseyin;Alkim, Canan
通讯作者：
Alkim, Canan
影响因子：
7.8
作者：
Dinarello CA;van der Meer JW
通讯作者：
van der Meer JW
影响因子：
4.4
作者：
JORGENSEN, WL;CHANDRASEKHAR, J;KLEIN, ML
通讯作者：
KLEIN, ML