a novel inhibitor of human la protein with anti-hbv activity discovered by structure-based virtual screening and in vitro evaluation一种新型抑制剂的人类la蛋白质anti-hbv活动发现的基于结构的虚拟筛选和体外评价.pdfVIP

A Novel Inhibitor of Human La Protein with Anti-HBV Activity Discovered by Structure-Based Virtual Screening and In Vitro Evaluation 1 2 2 3 1 2 Jing Tang , Zhi-Min Huang , Ying-Yi Chen , Zhao-Hui Zhang , Gao-Lin Liu *, Jian Zhang * 1 Department of Pharmacy, First People’s Hospital Affiliated with Shanghai JiaoTong University, Shanghai, China, 2 Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis, Chinese Ministry of Education, Shanghai JiaoTong University School of Medicine, Shanghai, China, 3 Department of Urology, Ruijin Hospital Luwan Branch Affiliated with Shanghai JiaoTong University School of Medicine, Shanghai, China Abstract Background: Over 350 million people worldwide are infected with hepatitis B virus (HBV), a major cause of liver failure and hepatocellular carcinoma. Current therapeutic agents are highly effective, but are also associated with development of viral resistance. Therefore, strategies for identifying other anti-HBV agents with specific, but distinctive mechanisms of action are needed. The human La (hLa) protein, which forms a stabilizing complex with HBV RNA ribonucleoprotein to promote HBV replication, is a promising target of molecular therapy. Aims: This study aimed to discover novel inhibitors of hLa that could inhibit HBV replication and expression. Methods: A multistage molecular docking approach was used to screen a Specs database and an in-house library against hLa binding sites. Sequential in vitro evaluations were performed to detect potential compounds with high scores in HepG2.2.15 cells. Results: Of the 26 potential compounds with high scores chosen for experimental verification, 12 had HBV DNA inhibition ratios of less than 50% with P,0.05. Six had significant inhib