发现Daclatasvir是潜在的PD-L1抑制剂，可重新利用药物
Discovery of Daclatasvir as a potential PD-L1 inhibitor from drug repurposing
影响因子:4.70000
分区:医学2区 / 有机化学1区 生化与分子生物学2区
发表日期:2024 Dec
作者:
Mengmeng Sun, Shixuan Lv, Yanyan Pan, Qiling Song, Chunyan Ma, Menglin Yu, Xinru Gao, Xiuhan Guo, Shisheng Wang, Zhigang Gao, Shuai Wang, Qingwei Meng, Li Zhang, Yueqing Li
摘要
这项研究采用药物重新定位策略来发现新型的PD-L1小分子抑制剂。建立了3D-QSAR药效团模型，并随后通过各种方法验证了适用于虚拟筛选的强大模型。使用Hypo1 Toscreen来自药品银行数据库的7,475种化合物的库，从而导致分子对接后用PD-L1.19化合物鉴定283个分子进行了HTRF测定，其中15种显示了PD-1/PD-1/PD-L1相互作用的抑制程度。化合物2202,2204,2207和2208通过SPR实验进一步证实可以与PD-L1结合。其中，Compound2204（Daclatasvir，KD =11.4μm）对人PD-L1的亲和力高于对照化合物BMS-1。在HEPG2/Jurkat细胞共培养模型中，Daclatasvir有效地激活了Jurkat细胞以杀死HEPG2细胞。在小鼠H22肝细胞肿瘤模型中，daclatasvir显着抑制肿瘤的生长（TGI = 53.4％，剂量为100 mg/kg）。当与Lenvatinib结合使用时，其抗肿瘤效应更为明显（TGI = 85.1％）。脾细胞和肿瘤细胞的流式细胞仪分析表明，Daclatasvir在这两个模型中都激活了免疫系统。总而言之，Daclatasvir被确定为一种新型的PD-L1Small分子抑制剂。
Abstract
This study employed a drug repositioning strategy to discover novel PD-L1 small molecule inhibitors. 3D-QSAR pharmacophore models were establishedand subsequently validated through various means to select a robust model, Hypo-1, suitable for virtual screening. Hypo1 was used toscreen a library of 7,475 compounds from the Drugbank database, leading to the identification of 283 molecules following molecular docking with PD-L1.19 compounds underwent HTRF assays, with 15 showing varying degrees of inhibition of the PD-1/PD-L1 interaction. Compounds2202,2204,2207, and2208were further confirmed to bind to PD-L1 using SPR experiments. Among them, compound2204(Daclatasvir, KD = 11.4 μM) showeda higher affinity for human PD-L1 than the control compound BMS-1. In the HepG2/Jurkat cell co-culture model, Daclatasvir effectively activated Jurkat cells to kill HepG2 cells. In the mouse H22 hepatocellular tumor model, Daclatasvir significantly inhibited tumor growth (TGI = 53.4 % at a dose of 100 mg/kg). Its anti-tumor effect was more pronounced when combined with Lenvatinib (TGI = 85.1 %). Flow cytometry analysis of splenocytes and tumor cells indicated that Daclatasvir activated the immune system in both models. In summary, Daclatasvir was identified as a novel PD-L1small molecule inhibitor.