Identification of Phelligridin-Based Compounds as Novel Human CD73 Inhibitors

Lyu，Sifan1; Zhao，Yunshuo1; Zeng，Xiao2; Chen，Xiaotong1; Meng，Qingqing1; Ding，Zhe1; Zhao，Wenshan1; Qi，Yuanming1; Gao，Yanfeng3; Du，Jiangfeng1

2021

10.1021/acs.jcim.0c00961

Journal of Chemical Information and Modeling   影响因子和分区

1549-9596

1520-5142

As an emerging immune checkpoint, CD73 has received more attention in the past decade. Inhibition of CD73 enzymatic activity can enhance antitumor immunity. Several CD73 inhibitors have been identified by in vitro assays in recent years, but they remain premature for clinical application, indicating that more novel CD73 inhibitors should be studied. Herein, we aimed to identify novel CD73 inhibitors that hopefully are suitable drug candidates by using computer-aided drug discovery and enzymatic-based assays. Five-hundred molecules with high binding affinity were retrieved from the Chemdiv-Plus database by using a structure-based virtual screening approach. Then, we analyzed the drug properties of these molecules and obtained 68 small molecules based on the oral noncentral nervous system (CNS) drug profile. The inhibition rates of these molecules against CD73 enzymatic activities were determined at a concentration of 100 μM, and 20 molecules had an inhibition rate greater than 20%, eight of which were dose-dependent, with IC50 values of 6.72-172.1 μM. Among the screening hits, phelligridin-based compounds had the best experimental inhibition values. Modeling studies indicate that the phelligridin group is sandwiched by the rings of F417 and F500 residues. The identified inhibitors have a molecular weight of approximately 500 Dal and are predicted to form primarily hydrogen bonds with CD73 in addition to hydrophobic stacking interactions. In conclusion, novel inhibitors with satisfactory drug properties may serve as lead compounds for the development of CD73-targeting drugs, and the binding modes may provide insight for phelligridin-based drug design.

SCI ; EI

英语

其他

WOS:000636723700021

2-s2.0-85103305898

Scopus

1.School of Life Sciences,Zhengzhou University,Zhengzhou,450001,China
2.Center Lab of Longhua Branch and Department of Infectious Disease,Shenzhen People's Hospital (The Second Clinical Medical College,Jinan University,The First Affiliated Hospital,Southern University of Science and Technology),Shenzhen, Guangdong,518020,China
3.School of Pharmaceutical Sciences (Shenzhen),Sun Yat-sen University,Shenzhen,518107,China

Lyu，Sifan,Zhao，Yunshuo,Zeng，Xiao,et al. Identification of Phelligridin-Based Compounds as Novel Human CD73 Inhibitors[J]. Journal of Chemical Information and Modeling,2021.

Lyu，Sifan.,Zhao，Yunshuo.,Zeng，Xiao.,Chen，Xiaotong.,Meng，Qingqing.,...&Du，Jiangfeng.(2021).Identification of Phelligridin-Based Compounds as Novel Human CD73 Inhibitors.Journal of Chemical Information and Modeling.

Lyu，Sifan,et al."Identification of Phelligridin-Based Compounds as Novel Human CD73 Inhibitors".Journal of Chemical Information and Modeling (2021).