Molecules, Vol. 26, Pages 1350: Inhibitor Development Against p7 Channel in Hepatitis C Virus

Molecules, Vol. 26, Pages 1350: Inhibitor Development Against p7 Channel in Hepatitis C Virus Molecules doi: 10.3390/molecules26051350 Authors: Shukun Wei Xiaoyou Hu Lingyu Du Linlin Zhao Hongjuan Xue Chaolun Liu James J. Chou Jin Zhong Yimin Tong Shuqing Wang Bo OuYang 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 studie...
Source: Molecules - Category: Chemistry Authors: Tags: Article Source Type: research