Identification of Small-Molecule Inhibitors of Fibroblast Growth Factor 23 Signaling via In Silico Hot Spot Prediction and Molecular Docking to α-Klotho.
Identification of Small-Molecule Inhibitors of Fibroblast Growth Factor 23 Signaling via In Silico Hot Spot Prediction and Molecular Docking to α-Klotho.
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DOI：
10.1021/acs.jcim.2c00633
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发表时间：
2022-08-08
影响因子：
5.6
通讯作者：
Petridis, Loukas
中科院分区：
文献类型：
--
作者：
Liu, Shih-Hsien;Xiao, Zhousheng;Mishra, Sambit K.;Mitchell, Julie C.;Smith, Jeremy C.;Quarles, L. Darryl;Petridis, Loukas
成纤维细胞生长因子23（FGF 23）是用于治疗遗传性和获得性低磷酸盐血症病症的治疗靶标，所述遗传性和获得性低磷酸盐血症病症分别诸如X连锁低磷酸盐血症（XLH）佝偻病和肿瘤诱导的骨软化症（TIO）。FGF 23诱导的低磷酸盐血症由通过FGF 23、FGF受体（FGFR）和α-Klotho形成的三元复合物的信号传导介导。目前，过量FGF 23的病症用FGF 23阻断抗体burosumab治疗。破坏三元复合物形成所必需的蛋白质/蛋白质相互作用的小分子药物提供了破坏FGF 23信号传导的替代方案。在这项研究中，FGF 23：α-Klotho界面被靶向鉴定小分子蛋白质/蛋白质相互作用抑制剂，因为计算预测它在α-Klotho上具有大部分热点和两个可药用残基。我们进一步确定了α-Klotho的KL 1结构域上的Tyr 433作为一个有希望的热点，α-Klotho作为该界面上适当的药物结合靶点。随后，我们将来自ZINC数据库的约550万种化合物与来自三元晶体结构的α-Klotho的界面区域进行了计算机对接。对接后，基于与α-Klotho的最低结合自由能和与Tyr 433的最大接触次数，分别有24和20种化合物进入最终列表。五个化合物进行了实验评估，其FGF 23介导的细胞外信号调节激酶（ERK）的活动在体外，和这些减少的活动显着。预测这两种化合物均与α-Klotho具有良好的结合亲和力，但与热点Tyr 433没有大量接触。实验发现ZINC 12409120可破坏FGF 23：α-Klotho相互作用，使FGF 23介导的ERK活性降低70%，半数最大抑制浓度（IC 50）为5.0 ± 0.23 μM。ZINC 12409120：α-Klotho复合物的分子动力学（MD）模拟（从计算机模拟对接位姿开始）显示，配体同时与α-Klotho的KL 1结构域、KL 1-KL 2接头和KL 2结构域上的残基接触，从而可能破坏α-Klotho的常规功能并阻碍FGF 23：α-Klotho相互作用。ZINC 12409120是电极导线优化的候选产品。
Fibroblast growth factor 23 (FGF23) is a therapeutic target for treating hereditary and acquired hypophosphatemic disorders, such as X-linked hypophosphatemic (XLH) rickets and tumor-induced osteomalacia (TIO), respectively. FGF23-induced hypophosphatemia is mediated by signaling through a ternary complex formed by FGF23, the FGF receptor (FGFR), and α-Klotho. Currently, disorders of excess FGF23 are treated with an FGF23-blocking antibody, burosumab. Small-molecule drugs that disrupt protein/protein interactions necessary for the ternary complex formation offer an alternative to disrupting FGF23 signaling. In this study, the FGF23:α-Klotho interface was targeted to identify small-molecule protein/protein interaction inhibitors since it was computationally predicted to have a large fraction of hot spots and two druggable residues on α-Klotho. We further identified Tyr433 on the KL1 domain of α-Klotho as a promising hot spot and α-Klotho as an appropriate drug-binding target at this interface. Subsequently, we performed in silico docking of ~5.5 million compounds from the ZINC database to the interface region of α-Klotho from the ternary crystal structure. Following docking, 24 and 20 compounds were in the final list based on the lowest binding free energies to α-Klotho and the largest number of contacts with Tyr433, respectively. Five compounds were assessed experimentally by their FGF23-mediated extracellular signal-regulated kinase (ERK) activities in vitro, and two of these reduced activities significantly. Both these compounds were predicted to have favorable binding affinities to α-Klotho but not have a large number of contacts with the hot spot Tyr433. ZINC12409120 was found experimentally to disrupt FGF23:α-Klotho interaction to reduce FGF23-mediated ERK activities by 70% and have a half maximal inhibitory concentration (IC50) of 5.0 ± 0.23 μM. Molecular dynamics (MD) simulations of the ZINC12409120:α-Klotho complex starting from in silico docking poses reveal that the ligand exhibits contacts with residues on the KL1 domain, the KL1–KL2 linker, and the KL2 domain of α-Klotho simultaneously, thereby possibly disrupting the regular function of α-Klotho and impeding FGF23:α-Klotho interaction. ZINC12409120 is a candidate for lead optimization.
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影响因子：
4.1
作者：
Colares Neto, Guido de Paula;Yamauchi, Fernando Ide;Martin, Regina Matsunaga
通讯作者：
Martin, Regina Matsunaga
影响因子：
8.8
作者：
Agrawal, Archita;Ni, Pu;DiMarchi, Richard D.
通讯作者：
DiMarchi, Richard D.
影响因子：
4.6
作者：
Daina A;Michielin O;Zoete V
通讯作者：
Zoete V
影响因子：
5.5
作者：
Best, Robert B.;Zhu, Xiao;Shim, Jihyun;Lopes, Pedro E. M.;Mittal, Jeetain;Feig, Michael;MacKerell, Alexander D., Jr.
通讯作者：
MacKerell, Alexander D., Jr.
DOI：
10.1158/1078-0432.ccr-11-1468
发表时间：
2011-10-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Chaft JE;Oxnard GR;Sima CS;Kris MG;Miller VA;Riely GJ
通讯作者：
Riely GJ