In this paper, 42 4-hydroxyamino α-pyranone carboxamide analogues as Hepatitis C Virus(HCV) inhibitor 3 D-QSAR model was built based on Topomer CoMFA. The non-cross-validation(r2), cross-validation(q2), correlation c...In this paper, 42 4-hydroxyamino α-pyranone carboxamide analogues as Hepatitis C Virus(HCV) inhibitor 3 D-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(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 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.展开更多
Topomer comparative molecular field analysis(Topomer Co MFA)and holographic quantitative structure-activity relationship(HQSAR)for 1302,5-diketopiperazine derivatives were used to build a three-dimensional quantitativ...Topomer comparative molecular field analysis(Topomer Co MFA)and holographic quantitative structure-activity relationship(HQSAR)for 1302,5-diketopiperazine derivatives were used to build a three-dimensional quantitative structure-activity relationship(3D-QSAR)model.The results show that the models have high predictive ability.For Topomer CoMFA,the cross-validated q^2 value is 0.710 and the non-cross-validated r^2 value is 0.834.The most effective HQSAR model shows that the cross-validation q^2 value is 0.700,the non-cross-validated r^2 value is 0.815,and the best hologram length value is 353 using connections and bonds as fragment distinctions.50 highly active 2,5-diketopiperazine derivatives were designed based on the three-dimensional equipotential map and HQSAR color code map.Finally,the molecular docking method was also used to study the interactions of these new molecules by docking the ligands into the diketopiperazine active site,which revealed the likely bioactive conformations.This study showed that there are extensive interactions between the new molecule and Arg156,Arg122 residues in the active site of diketopiperazine.These results provide useful insights for the design of potent of the new 2,5-diketopiperazine derivatives.展开更多
基金supported by the National Natural Science Foundation of China (21475081)the Natural Science Foundation of Shaanxi Province (2019JM-237)the Graduate Innovation Fund of Shaanxi University of Science and Technology。
文摘In this paper, 42 4-hydroxyamino α-pyranone carboxamide analogues as Hepatitis C Virus(HCV) inhibitor 3 D-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(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 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.
基金supported by the National Natural Science Funds of China(21475081)the Natural Science Foundation of Shaanxi Province(2019JM-237)the Graduate Innovation Fund of Shaanxi University of Science and Technology。
文摘Topomer comparative molecular field analysis(Topomer Co MFA)and holographic quantitative structure-activity relationship(HQSAR)for 1302,5-diketopiperazine derivatives were used to build a three-dimensional quantitative structure-activity relationship(3D-QSAR)model.The results show that the models have high predictive ability.For Topomer CoMFA,the cross-validated q^2 value is 0.710 and the non-cross-validated r^2 value is 0.834.The most effective HQSAR model shows that the cross-validation q^2 value is 0.700,the non-cross-validated r^2 value is 0.815,and the best hologram length value is 353 using connections and bonds as fragment distinctions.50 highly active 2,5-diketopiperazine derivatives were designed based on the three-dimensional equipotential map and HQSAR color code map.Finally,the molecular docking method was also used to study the interactions of these new molecules by docking the ligands into the diketopiperazine active site,which revealed the likely bioactive conformations.This study showed that there are extensive interactions between the new molecule and Arg156,Arg122 residues in the active site of diketopiperazine.These results provide useful insights for the design of potent of the new 2,5-diketopiperazine derivatives.
