Three-dimensional quantitative structure-activity relationship （3D-QSAR） and docking studies of a series of novel dioxopyrrolinyl-amino-pyrimidine derivatives, which are potential dual inhibitors mediating a transcr...Three-dimensional quantitative structure-activity relationship （3D-QSAR） and docking studies of a series of novel dioxopyrrolinyl-amino-pyrimidine derivatives, which are potential dual inhibitors mediating a transcriptional activation towards protein-1 （AP-1） and nuclear factor kappa B （NF-κB）, have been carried out. The QS, AR models established by comparative molecular field analysis （CoMFA） and comparative molecular similarity index analysis （CoMSIA） show a good predictive ability with cross-validated coefficients q2 of 0.644 and 0.636, respectively. The docking result shows that there are quite lower average values of the flexible and rigid energy scores on the selected binding sites, meanwhile, it further shows that the binding sites just fall on the joint regions between AP-1 （and NF-κB） and DNA. The reason that these analogues have inhibition function towards AP-I and NF-κB is that their existence on these joint regions can effectively prevent free AP-I and NF-κB from binding to DNA. These results can offer a valuable theoretical reference to the pharmaceutical molecular design as well as the action mechanism analysis.展开更多
Transthyretin(TTR),a plasma protein with a tetramer structure,could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer.These amyloidogenesis c...Transthyretin(TTR),a plasma protein with a tetramer structure,could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer.These amyloidogenesis can be inhibited by small molecules which bind to the central channel of TTR.A number of small molecules like 2-arylbenzoxazoles(ABZ)analogues are proposed as promising therapeutic strategy to treat amyloidosis.In this work,comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)three-dimensional quantitative structure-activity relationship(3D-QSAR)and docking studies were performed on series of 2-arylbenzoxazoles(ABZ)and linker-Y analogues to investigate the inhibitory activities of TTR amyloidogenesis at atomic level.Significant correlation coefficients for ABZ series(CoMFA,r2=0.877,q2=0.431;CoMSIA,r2=0.836,q2=0.447)and those for linker-Y series(CoMFA,r2=0.828,q2=0.522;CoMSIA,r2=0.800,q2=0.493)were obtained,and the generated models were validated using test sets.In addition,docking studies on 6 compounds binding to TTR were performed to analyze the forward or reverse binding mode and interactions between molecules and TTR.These results from 3D-QSAR and docking studies have great significance for designing novel TTR amyloidogenesis inhibitors in the future.展开更多
基金Acknowledgments： The authors are pleased to thank the financial supports of the National Natural Science Foundation of China （Nos.： 20673148 and 90608012）. We heartily thank the Molecular Discovery Ltd. for giving us the Dock 6.0 program as a freewarc. The authors are also pleased to thank the College of Life Sciences, Sun Yat-Sen University for the Sybyl 6.9 computation environment support.
文摘Three-dimensional quantitative structure-activity relationship （3D-QSAR） and docking studies of a series of novel dioxopyrrolinyl-amino-pyrimidine derivatives, which are potential dual inhibitors mediating a transcriptional activation towards protein-1 （AP-1） and nuclear factor kappa B （NF-κB）, have been carried out. The QS, AR models established by comparative molecular field analysis （CoMFA） and comparative molecular similarity index analysis （CoMSIA） show a good predictive ability with cross-validated coefficients q2 of 0.644 and 0.636, respectively. The docking result shows that there are quite lower average values of the flexible and rigid energy scores on the selected binding sites, meanwhile, it further shows that the binding sites just fall on the joint regions between AP-1 （and NF-κB） and DNA. The reason that these analogues have inhibition function towards AP-I and NF-κB is that their existence on these joint regions can effectively prevent free AP-I and NF-κB from binding to DNA. These results can offer a valuable theoretical reference to the pharmaceutical molecular design as well as the action mechanism analysis.
基金supported by the National Natural Science Foundation of China(21072018)the Fundamental Research Funds for the Central Universities(ZY1213)the Foundation of State Key Laboratory of Natural and Biomimetic Drugs(K20120202)
文摘Transthyretin(TTR),a plasma protein with a tetramer structure,could form amyloid fibril associated with several human diseases through the dissociation of tetramer and the misfolding of monomer.These amyloidogenesis can be inhibited by small molecules which bind to the central channel of TTR.A number of small molecules like 2-arylbenzoxazoles(ABZ)analogues are proposed as promising therapeutic strategy to treat amyloidosis.In this work,comparative molecular field analysis(CoMFA)and comparative molecular similarity indices analysis(CoMSIA)three-dimensional quantitative structure-activity relationship(3D-QSAR)and docking studies were performed on series of 2-arylbenzoxazoles(ABZ)and linker-Y analogues to investigate the inhibitory activities of TTR amyloidogenesis at atomic level.Significant correlation coefficients for ABZ series(CoMFA,r2=0.877,q2=0.431;CoMSIA,r2=0.836,q2=0.447)and those for linker-Y series(CoMFA,r2=0.828,q2=0.522;CoMSIA,r2=0.800,q2=0.493)were obtained,and the generated models were validated using test sets.In addition,docking studies on 6 compounds binding to TTR were performed to analyze the forward or reverse binding mode and interactions between molecules and TTR.These results from 3D-QSAR and docking studies have great significance for designing novel TTR amyloidogenesis inhibitors in the future.
