Identification of novel PD-1/PD-L1 small molecule inhibitors: virtual screening, synthesis and in vitro characterisation

被引:2
作者
Wu, Tingting [1 ,2 ]
Cheng, Hu [1 ]
Sima, Lijie [3 ]
Wang, Zhongyuan [4 ]
Ouyang, Weiwei [5 ,6 ]
Wang, Jianta [1 ]
Hou, Yunlei [7 ]
Zhao, Dongsheng [1 ]
Liao, Weike [1 ]
Hu, Chujiao [1 ]
机构
[1] Guizhou Med Univ, Guizhou Prov Engn Technol Res Ctr Chem Drug R&D, Guiyang 550004, Peoples R China
[2] Zhejiang Prov Peoples Hosp Bijie Hosp, Dept Pharm, Bijie, Peoples R China
[3] First Peoples Hosp Huaihua, Dept Oncol, Huaihua, Peoples R China
[4] Guizhou Prov Peoples Hosp, Dept Pharm, Guiyang, Peoples R China
[5] Guizhou Med Univ, Affiliated Hosp, Dept Oncol, Guiyang, Peoples R China
[6] Guizhou Med Univ, Canc Hosp, Guiyang, Peoples R China
[7] Shenyang Pharmaceut Univ, Key Lab Struct Based Drug Design & Discovery, Minist Educ, Shenyang, Peoples R China
基金
美国国家科学基金会;
关键词
Immune checkpoint; PD-1/PD-L1; inhibitors; virtual screening; molecular dynamics simulation;
D O I
10.1080/14756366.2024.2353711
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The PD-1/PD-L1 pathway is considered as one of the most promising immune checkpoints in tumour immunotherapy. However, researchers are faced with the inherent limitations of antibodies, driving them to pursue PD-L1 small molecule inhibitors. Virtual screening followed by experimental validation is a proven approach to discover active compounds. In this study, we employed multistage virtual screening methods to screen multiple compound databases to predict new PD-1/PD-L1 ligands. 35 compounds were proposed by combined analysis of fitness scores, interaction pattern and MM-GBSA binding affinities. Enzymatic assay confirmed that 10 out of 35 ligands were potential PD-L1 inhibitors, with inhibitory rate higher than 50% at the concentration of 30 mu M. Among them, ZDS20 was identified as the most effective inhibitor with low micromolar activity (IC50 = 3.27 mu M). Altogether, ZDS20 carrying novel scaffold was identified and could serve as a lead for the development of new classes of PD-L1 inhibitors.
引用
收藏
页数:23
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