Inhibitor Development against p7 Channel in Hepatitis C Virus

doi:10.3390/molecules26051350

	Inhibitor Development against p7 Channel in Hepatitis C Virus
	Wei, Shukun 1,2; Hu, Xiaoyou 2,3; Du, Lingyu 1; Zhao, Linlin 1,4; Xue, Hongjuan 5; Liu, Chaolun6 ; Chou, James J.4; Zhong, Jin2,3,6 ; Tong, Yimin 3; Wang, Shuqing 7; OuYang, Bo 1,2
	2021-03
发表期刊	MOLECULES
EISSN	1420-3049
卷号	26 期号:5
发表状态	已发表
DOI	10.3390/molecules26051350
摘要	Hepatitis C Virus (HCV) is the key cause of chronic and severe liver diseases. The recent direct-acting antiviral agents have shown the clinical success on HCV-related diseases, but the rapid HCV mutations of the virus highlight the sustaining necessity to develop new drugs. p7, the viroporin protein from HCV, has been sought after as a potential anti-HCV drug target. Several classes of compounds, such as amantadine and rimantadine have been testified for p7 inhibition. However, the efficacies of these compounds are not high. Here, we screened some novel p7 inhibitors with amantadine scaffold for the inhibitor development. The dissociation constant (Kd) of 42 ARD-series compounds were determined by nuclear magnetic resonance (NMR) titrations. The efficacies of the two best inhibitors, ARD87 and ARD112, were further confirmed using viral production assay. The binding mode analysis and binding stability for the strongest inhibitor were deciphered by molecular dynamics (MD) simulation. These ARD-series compounds together with 49 previously published compounds were further analyzed by molecular docking. Key pharmacophores were identified among the structure-similar compounds. Our studies suggest that different functional groups are highly correlated with the efficacy for inhibiting p7 of HCV, in which hydrophobic interactions are the dominant forces for the inhibition potency. Our findings provide guiding principles for designing higher affinity inhibitors of p7 as potential anti-HCV drug candidates.
关键词	rational design p7 inhibitors docking MD simulation HCV production
URL	查看原文
收录类别	SCI ; SCIE
语种	英语
WOS研究方向	Biochemistry & Molecular Biology ; Chemistry, Multidisciplinary
WOS类目	Biochemistry & Molecular Biology ; Chemistry
WOS记录号	WOS:000628405300001
出版者	MDPI
原始文献类型	Article
引用统计
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/126101
专题	生命科学与技术学院_特聘教授组_钟劲组生命科学与技术学院_硕士生
通讯作者	Tong, Yimin; Wang, Shuqing; OuYang, Bo
作者单位	1.Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Ctr Excellence Mol Cell Sci,State Key Lab Mol Bio, 333 Haike Rd, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing 100049, Peoples R China; 3.Chinese Acad Sci, Inst Pasteur Shanghai, CAS Key Lab Mol Virol & Immunol, Shanghai 200031, Peoples R China; 4.Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 USA; 5.Chinese Acad Sci, Shanghai Adv Res Inst, ZhangJiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China; 6.ShanghaiTech Univ, Shanghai 201210, Peoples R China; 7.Tianjin Med Univ, Sch Pharm, Tianjin 300070, Peoples R China
推荐引用方式 GB/T 7714	Wei, Shukun,Hu, Xiaoyou,Du, Lingyu,et al. Inhibitor Development against p7 Channel in Hepatitis C Virus[J]. MOLECULES,2021,26(5).
APA	Wei, Shukun.,Hu, Xiaoyou.,Du, Lingyu.,Zhao, Linlin.,Xue, Hongjuan.,...&OuYang, Bo.(2021).Inhibitor Development against p7 Channel in Hepatitis C Virus.MOLECULES,26(5).
MLA	Wei, Shukun,et al."Inhibitor Development against p7 Channel in Hepatitis C Virus".MOLECULES 26.5(2021).