Department of Medical Research Center, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.
Department of Orthopaedics, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China.
Biomed Res Int. 2021 Nov 22;2021:3664564. doi: 10.1155/2021/3664564. eCollection 2021.
Tumor necrosis factor- is a common cytokine that increases in inflammatory processes, slows the differentiation of bone formation, and induces osteodystrophy in the long-term inflammatory microenvironment. Our previous study confirmed that the Elongation protein 2 (ELP2) plays a significant role in osteogenesis and osteogenic differentiation, which is considered a drug discovery target in diseases related to bone formation and differentiation. In this study, we applied an in silico virtual screening method to select molecules that bind to the ELP2 protein from a chemical drug molecule library and obtained 95 candidates. Then, we included 11 candidates by observing the docking patterns and the noncovalent bonds. The binding affinity of the ELP2 protein with the candidate compounds was examined by SPR analysis, and 5 out of 11 compounds performed good binding affinity to the mouse ELP2 protein. After in vitro cell differentiation assay, candidates 2# and 5# were shown to reduce differentiation inhibition after tumor necrosis factor- stimulation, allowing further optimization and development for potential clinical treatment of inflammation-mediated orthopedic diseases.
肿瘤坏死因子-α是一种常见的细胞因子，可在炎症过程中增加，减缓骨形成的分化，并在长期炎症微环境中诱导骨营养不良。我们之前的研究证实伸长蛋白 2（ELP2）在成骨和成骨分化中发挥重要作用，被认为是与骨形成和分化相关疾病的药物发现靶点。在这项研究中，我们应用计算机虚拟筛选方法从化学药物分子文库中筛选与 ELP2 蛋白结合的分子，得到 95 个候选物。然后，我们观察对接模式和非共价键，纳入了 11 个候选物。通过 SPR 分析检测 ELP2 蛋白与候选化合物的结合亲和力，11 个化合物中有 5 个对小鼠 ELP2 蛋白具有良好的结合亲和力。经过体外细胞分化试验，候选物 2#和 5#在肿瘤坏死因子-α刺激后显示出减少分化抑制的作用，为炎症介导的骨科疾病的潜在临床治疗提供了进一步的优化和发展。
