Discovery of novel non-steroidal selective glucocorticoid receptor modulators by structure- and IGN-based virtual screening, structural optimization, and biological evaluation
Discovery of novel non-steroidal selective glucocorticoid receptor modulators by structure- and IGN-based virtual screening, structural optimization, and biological evaluation
复制标题
通过基于结构和 IGN 的虚拟筛选、结构优化和生物学评价发现新型非甾体选择性糖皮质激素受体调节剂
DOI：
10.1016/j.ejmech.2022.114382
复制
发表时间：
2022-04-25
影响因子：
6.7
通讯作者：
Li, Dan
中科院分区：
文献类型：
--
作者：
Hu, Xueping;Pang, Jinping;Li, Dan
糖皮质激素（GC）是最常用的抗炎药物。然而，它们优异的治疗效果常常伴随着不希望的副作用。为了发现选择性糖皮质激素受体调节剂（SGRM），其优先诱导具有很少或没有反式激活活性的反式阻遏，通过结合分子对接和InteractionGraphNet（IGN）重新评分进行基于结构的虚拟筛选，并鉴定化合物HP 210。HP 210不诱导GR的反式激活功能，但仍作用于NF-κ B B介导的系留反式抑制功能（IC 50 = 2.32 μ M），并抑制促炎细胞因子IL-1 β和IL-6的分泌。与地塞米松相比，HP 210与骨代谢相关的盐皮质激素受体和孕酮受体无交叉活性，对骨保护素无明显影响，副作用明显减少。然后，在分子动力学模拟和结合自由能计算的指导下，发现了具有超过两倍高的反式阻遏活性（IC 50 = 0.99 μ M）的化合物HP 210_b4。本研究报道了一组非甾体类新型支架SGRM，为开发新型抗炎药物提供了有价值的线索。
Glucocorticoids (GCs) are the most commonly used anti-inflammatory drugs. However, their excellent therapeutic effects are often accompanied by undesirable side effects. To discover selective glucocorticoid receptor modulators (SGRMs) that preferentially induce transrepression with little or no transactivation activity, a structure-based virtual screening by combining molecular docking and InteractionGraphNet (IGN) rescoring was performed, and compound HP210 was identified. HP210 did not induce the transactivation functions of GR while still acted on the NF-kappa B mediated tethered transrepression function (IC50 = 2.32 mu M), and suppressed the secretion of pro-inflammation cytokines IL-1 beta and IL-6. Compared with dexamethasone, HP210 showed no cross activities with phylogenetically related mineralcorticoid receptor and progesterone receptor and no significant effect on osteoprotegerin, exhibiting a reduced side-effect profile. Then, guided by the molecular dynamics simulations and binding free energy calculations, compound HP210_b4 with over two-fold higher transrepression activity (IC50 = 0.99 mu M) was discovered. This study reported a group of non-steroidal new-scaffold SGRMs, providing valuable clues for the development of novel anti-inflammatory drugs.