Novel Natural Inhibitors Targeting Enhancer of Zeste Homolog 2: A Comprehensive Structural Biology Research

Frontiers in Oncology

Yunlong Zhao¹  Rui Xu²  Min Jiang³  Yanjiang Yin⁴  Yingjing Zhao⁵  Min Chao⁶  Liang Wang⁶  Shilei Zhang⁷  Ming Yan⁷  Ziyi Ding⁷  Dong Wang⁷  Weihang Li⁷  Ke Lei⁷  Changbin Yang⁸  Hongzhe Zhao⁹ 

[1]College of Clinical Medicine, China-Japan Union Hospital of Jilin University, Changchun, China

[2]Department of Endocrinology, Shanghai National Research Center for Endocrine and Metabolic Disease, State Key Laboratory of Medical Genomics, Shanghai Institute for Endocrine and Metabolic Disease, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China

[3]Department of General Surgery, Zhen an County People’s Hospital, Shangluo, China

[4]Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China

[5]Department of Intensive Care Unit, Nanjing First Hospital, Nanjing Medical University, Nanjing, China

[6]Department of Neurosurgery, Tangdu Hospital of Fourth Military Medical University, Xi’an, China

[7]Department of Orthopedic Surgery, Xijing Hospital, The Fourth Military Medical University, Xi’an, China

[8]Military Medical Innovation Center, The Fourth Military Medical University, Xi’an, China

[9]State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China

关键词: EZH2;    inhibitor;    histone methyltransferase;    structural biology;    virtual screening;   

DOI  :  10.3389/fonc.2021.741403

来源: DOAJ

【 摘 要 】

The enhancer of zeste homolog 2 (EZH2) is a methylated modification enzyme of Histone H3-Lys 27. The high expression of EZH2 in cells is closely related to the progression, invasion, and metastasis of neoplasm. Therefore, this target is gradually becoming one of the research hot spots of tumor pathogenesis, and the inhibitors of the EZH2 enzyme are expected to become new antitumor drugs. This study used a series of virtual screening technologies to calculate the affinity between the compounds obtained from the ZINC15 database and the target protein EZH2, the stability of the ligand–receptor complex. This experiment also predicted the toxicity and absorption, distribution, metabolism, and excretion (ADME) properties of the candidate drugs in order to obtain compounds with excellent pharmacological properties. Finally, the ligand–receptor complex under in vivo situation was estimated by molecular dynamics simulation to observe whether the complex could exist steadily in the body. The experimental results showed that the two natural compounds ZINC000004217536 and ZINC000003938642 could bind tightly to EZH2, and the ligand–receptor complex could exist stably in vivo. Moreover, these two compounds were calculated to be nontoxic. They also had a high degree of intestinal absorption and high bioavailability. In vitro experiments confirmed that drug ZINC000003938642 could inhibit the proliferation and migration of osteosarcoma, which could serve as potential lead compounds. Therefore, the discovery of these two natural products had broad prospects in the development of EZH2 inhibitors, providing new clues for the treatment or adjuvant treatment of tumors.

【 授权许可】

Unknown