药物重新定位发现达拉匹韦作为潜在的PD-L1抑制剂

Discovery of Daclatasvir as a potential PD-L1 inhibitor from drug repurposing

BIOORGANIC CHEMISTRY

影响因子:4.7

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

DOI: 10.1016/j.bioorg.2024.107874

摘要

本研究采用药物再定位策略，旨在发现新型的PD-L1小分子抑制剂。建立3D-QSAR药效团模型，并通过多种验证手段筛选出稳健模型Hypo-1，适用于虚拟筛选。利用Hypo-1筛选Drugbank数据库中的7475个化合物，经过分子对接后筛选出283个候选分子。19个候选分子进行了HTRF实验，其中15个显示出不同程度的抑制PD-1/PD-L1相互作用。进一步通过SPR实验确认2202、2204、2207和2208与PD-L1的结合，其中，2204（达拉匹韦，KD=11.4 μM）表现出比对照化合物BMS-1更高的亲和力。在HepG2/Jurkat细胞共培养模型中，达拉匹韦能有效激活Jurkat细胞杀伤HepG2细胞。在小鼠H22肝细胞肿瘤模型中，达拉匹韦显著抑制肿瘤生长（TGI=53.4%，剂量为100 mg/kg），与乐伐替尼联合使用时抗肿瘤效果更为显著（TGI=85.1%）。脾细胞和肿瘤细胞的流式细胞术分析显示，达拉匹韦在两种模型中均激活了免疫系统。综上所述，达拉匹韦被鉴定为新型的PD-L1小分子抑制剂。

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.