The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin rece...The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin receptor-like kinase 5, ALK5） inhibitors might have potential activity forthe treatment of relevant diseases. In this paper, the three-dimensional quantitativestructure-activity relationship （3D-QSAR） including comparative molecular field analysis （CoMFA）and comparative molecular similarity indices analysis （CoMSIA） were used to analyze thestructural requirements based on a dataset of 123 4-（[1,2,4]Triazolo[1,5-a]pyridine-6-yl）-5（3）-（6-methylpyridin-2-yl）imidazole analogues which acted as ALK5 inhibitors. The obtainedCoMFA model （q2= 0.652, r2= 0.876, r2pred = 0.845） and CoMSIA model （q^2= 0.648, r^2= 0.884,r^2pred = 0.853） were robust and satisfactory. The predictive ability of the derived models wasvalidated using a test set of 28 compounds. Additionally, potentially important structural featuresrequired to enhance activity were also elucidated by the contour maps derived from CoMFA andCoMSIA models. The results will be helpful to guide drug design strategies aimed at obtainingpotent and selective ALK5 inhibitors.展开更多
The p110α,catalytic subunit of PI3Ka,was the primary phosphoinositide 3-kinases(PI3Ks)isoform involved in oncogenic RTK signaling and tumorigenesis.In this study,the three-dimensional quantitative structure-activity ...The p110α,catalytic subunit of PI3Ka,was the primary phosphoinositide 3-kinases(PI3Ks)isoform involved in oncogenic RTK signaling and tumorigenesis.In this study,the three-dimensional quantitative structure-activity relationship(3D-QSAR),molecular docking and molecular dynamics simulation were employed to study the binding mode between 3-phenylsulfonylaminopyridine derivatives and PI3Kα.The stable and reliable 3D-QSAR models were constructed based on the application of the comparative molecular field analysis(CoMFA)model(q^(2)=0.704,r^(2)=0.994)and comparative molecular similarity index analysis(CoMSIA)model(q^(2)=0.804,r^(2)=0.996).The contour maps illustrated relationship between structure and biological activity.The conformation obtained after MD simulation was more stable than the docked conformation.MD simulation was performed in a more realistic environment,and was much closer to physiological conditions.As a result,five novel PI3Kα inhibitors were designed with better biological activity than the template compound 8.展开更多
基金supported by the Collaborative Innovation Center Project of Shanxi 'Astragalus' Resource Industrialization and Industrial Internationalization(No.HQXTCXZX2016-021)Natural Science Foundation of Shanxi Province(No.201601D011112)
文摘The transforming growth factor-β （TGF-β） plays a crucial role in the beginning andprogression of fibrosis in various organ systems such as lung, heart, liver and kidney. TGF-fl type Ireceptor kinase （activin receptor-like kinase 5, ALK5） inhibitors might have potential activity forthe treatment of relevant diseases. In this paper, the three-dimensional quantitativestructure-activity relationship （3D-QSAR） including comparative molecular field analysis （CoMFA）and comparative molecular similarity indices analysis （CoMSIA） were used to analyze thestructural requirements based on a dataset of 123 4-（[1,2,4]Triazolo[1,5-a]pyridine-6-yl）-5（3）-（6-methylpyridin-2-yl）imidazole analogues which acted as ALK5 inhibitors. The obtainedCoMFA model （q2= 0.652, r2= 0.876, r2pred = 0.845） and CoMSIA model （q^2= 0.648, r^2= 0.884,r^2pred = 0.853） were robust and satisfactory. The predictive ability of the derived models wasvalidated using a test set of 28 compounds. Additionally, potentially important structural featuresrequired to enhance activity were also elucidated by the contour maps derived from CoMFA andCoMSIA models. The results will be helpful to guide drug design strategies aimed at obtainingpotent and selective ALK5 inhibitors.
文摘The p110α,catalytic subunit of PI3Ka,was the primary phosphoinositide 3-kinases(PI3Ks)isoform involved in oncogenic RTK signaling and tumorigenesis.In this study,the three-dimensional quantitative structure-activity relationship(3D-QSAR),molecular docking and molecular dynamics simulation were employed to study the binding mode between 3-phenylsulfonylaminopyridine derivatives and PI3Kα.The stable and reliable 3D-QSAR models were constructed based on the application of the comparative molecular field analysis(CoMFA)model(q^(2)=0.704,r^(2)=0.994)and comparative molecular similarity index analysis(CoMSIA)model(q^(2)=0.804,r^(2)=0.996).The contour maps illustrated relationship between structure and biological activity.The conformation obtained after MD simulation was more stable than the docked conformation.MD simulation was performed in a more realistic environment,and was much closer to physiological conditions.As a result,five novel PI3Kα inhibitors were designed with better biological activity than the template compound 8.
