Citation: Jian-Bo TONG, Lu-Yang WU, Shan LEI, Tian-Hao WANG, Yang-Min MA. Molecular Modeling Studies of 4-Hydroxyamino α-Pyranone Carboxamide Analogues as Hepatitis C Virus Inhibitor Using 3D-QSAR and Molecular Docking[J]. Chinese Journal of Structural Chemistry, ;2020, 39(6): 1135-1145. doi: 10.14102/j.cnki.0254-5861.2011-2539 shu

Molecular Modeling Studies of 4-Hydroxyamino α-Pyranone Carboxamide Analogues as Hepatitis C Virus Inhibitor Using 3D-QSAR and Molecular Docking

Jian-Bo TONG ^{a, b,,} ,
Lu-Yang WU ^{a, b} ,
Shan LEI ^{a, b} ,
Tian-Hao WANG ^{a, b} ,
Yang-Min MA ^{a, b}

a.
College of Chemistry and Chemical Engineering, Shaanxi University of Science and Technology, Xi'an 710021, China
b.
Shaanxi Key Laboratory of Chemical Additives for Industry, Xi'an 710021, China

Corresponding author: Jian-Bo TONG, jianbotong@aliyun.com
Received Date: 19 July 2019
Accepted Date: 20 November 2019

Fund Project: the National Natural Science Foundation of China 21475081the Natural Science Foundation of Shaanxi Province 2019JM-237

Figures(7)

In this paper, 42 4-hydroxyamino α-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 external validation (Q_ext²), non-cross validated standard error (SD), standard error of prediction (SD_CV) 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 alternately 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.
- 3D-QSAR,
- 4-hydroxyamino α-pyranone carboxamide analogues,
- topomer CoMFA,
- molecule design,
- molecular docking
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