Presents an object-oriented NBO(node-block-object)data model for hypermedia system.It takes advantage of object-oriented method,encapsulates all multimedia information as well as link functions in one unit,It has succ...Presents an object-oriented NBO(node-block-object)data model for hypermedia system.It takes advantage of object-oriented method,encapsulates all multimedia information as well as link functions in one unit,It has successfully achieved cross link to offer much better flexibility and two-way link to realize forward and backward searching in hypermedia system navigation.A conditional relation on links has also been realized,that is very helpful for time sensitive multimedia information processing and multimedia object cooperation.展开更多
Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibi...Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.展开更多
文摘Presents an object-oriented NBO(node-block-object)data model for hypermedia system.It takes advantage of object-oriented method,encapsulates all multimedia information as well as link functions in one unit,It has successfully achieved cross link to offer much better flexibility and two-way link to realize forward and backward searching in hypermedia system navigation.A conditional relation on links has also been realized,that is very helpful for time sensitive multimedia information processing and multimedia object cooperation.
文摘Despite the efficacy of imatinib therapy in chronic myelogenous leukemia, the development of drug-resistant Abl mutants, especially the most difficult overcoming T3151 mutant, makes the search for new Abl T3151 inhibitors a very interesting challenge in medicinal chem- istry. In this work, a multistep computational framework combining the three dimensional quantitative structure-activity relationship （3D-QSAR）, molecular docking, molecular dy- namics （MD） simulation and binding free energy calculation, was performed to explore the structural requirements for the Abl T315I activities of benzimidazole/benzothiazole derivatives and the binding mechanism between the inhibitors and Abl T315I. The established 3D-QSAR models exhibited satisfactory internal and external predictability. Docking study elucidated the comformations of compounds and the key amino acid residues at the binding pocket, which were confirmed by MD simulation. The binding free energies correlated well with the experimental activities. The MM-GBSA energy decomposition revealed that the van der Waals interaction was the major driving force for the interaction between the ligands and Abl T3151. The hydrogen bond interactions between the inhibitors and Met318 also played an important role in stablizing the binding of compounds to Abl T315I. Finally, four new compounds with rather high Abl T3151 activities were designed and presented to experimenters for reference.
