据报道，gp130 信号级联在多种癌症中上调，这使得 gp130 成为抗癌药物开发的有吸引力的靶标。采用倒漏斗状方法以及各种基于结构的药物设计策略来发现和优化 gp130 的新型潜在抑制剂。该研究发现了 2 个配体 - 435 和 510，两者都对 gp130 D1 结构域表现出非常高的结合亲和力，该结构域控制细胞因子识别和相互作用，从而参与络合。所得的两种复合物随着时间的推移保持稳定，配体保持与靶标的稳定相互作用。这一推论是从他们的 RMSD、Rg、SASA 和 RMSF 分析中得出的。我们还根据主成分分析、表面能量和景观测试了蛋白质折叠模式。这些先导化合物还表现出比其母体化合物更有利的 ADMET 特征。与两种现有药物巴多昔芬和雷洛昔芬相比，这两种主要候选药物显示出更好的治疗效果。这两种潜在的先导化合物都可以在体外发挥其活性，并可用作潜在的抗癌治疗以及对抗 Covid-19 相关的细胞因子风暴。© 2023。作者获得 Springer 的独家许可瑞士自然股份公司。

An upregulation of the gp130-signalling cascade has been reported in multiple cancers, making gp130 an attractive target for the development of anticancer drugs. An inverted-funnel-like approach was utilised along with various structure-based drug designing strategies to discover and optimise novel potential inhibitors of gp130. The study resulted in the discovery of 2 ligands- 435 and 510, both of which exhibit a very high-binding affinity towards the gp130 D1 domain which controls cytokine recognition and interaction thus being involved in complexation. The two resulting complexes remained stable over time with the ligands maintaining a steady interaction with the target. This inference is drawn from their RMSD, Rg, SASA and RMSF analysis. We also tested the protein folding patterns based on their principal component analysis, energy of surface and landscape. The leads also displayed a more favourable ADMET profile than their parent compounds. The two lead candidates show a better therapeutic profile in comparison to the two existing drugs- bazedoxifene and raloxifene. Both these potential leads can be addressed for their activity in-vitro and can be used as a potential anti-cancer treatment as well as to combat Covid-19 related cytokine storm.© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.