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In this paper,42 4-hydroxyamino a-pyranone carboxamide analogues as Hepatitis C Virus (HCV) inhibitor 3D-QSAR model was built based on Topomer CoMFA.The non-cross-validation (r2),cross-validation (q2),correlation coefficient of extal validation (Qext2),non-cross validated standard error (SD),standard error of prediction (SDCV) and F are 0.909,0.615,0.967,0.13,0.28 and 37.287,respectively.The obtained Topomer CoMFA model has good estimation stability and prediction capability.Topomer Search was employed as a tool for virtual screening in lead-like compounds in the ZINC database.Then,6 R1 groups and 4 R2 groups with higher contribution values were employed to altately substitute for the R1 and R2 of the template compound 21 with the highest bioactivity.As a result,22 new molecules with higher activity than that of the template molecule were designed successfully.The Topomer Search technology could be effectively applied to screen and design new 4-hydroxyamino α-pyranone carboxamide analogues.The molecular docking method was also used to study the interactions of these drugs by docking the ligands into HCV active site,which revealed the likely bioactive conformations.This study showed extensive interactions between the 4-hydroxyamino α-pyranone carboxamide analogues and the active sites of HCV (residues TYR466,GLN384,TYR383 and ASP335).The design of potent new inhibitors of HCV can get useful insights from these results.