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
In order to screen out effective fungicides for controlling citrus canker,the control effects of 9 fungicides on Jinhong bingtang orange canker were studied.The results showed that 77%cupric calcium sulfate WP,30%copp...In order to screen out effective fungicides for controlling citrus canker,the control effects of 9 fungicides on Jinhong bingtang orange canker were studied.The results showed that 77%cupric calcium sulfate WP,30%copper oxychloride SC,46%copper hydroxide WG,30%thiodiazole-copper SC and 40%zinc thiazole SC had better comprehensive control effect on citrus canker,6%benziothiazolinone WG had an average effect,3%zhongshengmycin AS,2%kasugamycin AS and 33.5%oxine-copper SC had poor control effect.Therefore,fungicides could be used alternately or choose compounded preparation.In addition,adjuvants could be considered in use,which was an effective way to enhance efficacy,reduced dosage and delayed pesticide resistance.展开更多
A series of novel pyrazoles compounds were synthesized by the reaction of five kinds of substitute α-bromoacetophenone with pyrazole intermediates which was prepared by the reaction of chalcones and thiosemicarbazone...A series of novel pyrazoles compounds were synthesized by the reaction of five kinds of substitute α-bromoacetophenone with pyrazole intermediates which was prepared by the reaction of chalcones and thiosemicarbazones. This method has some advantages such as mild reaction condition, easy operation and higher yield. All the compounds were confirmed by elemental analysis, IR and 1H NMR.展开更多
Thiazolidinediones(TZDs),such as rosiglitazone(RSG),which activates peroxisome proliferator activated receptor-y(PPARy),are a potent class of oral antidiabetic agents with good durability.However,the clinical use of T...Thiazolidinediones(TZDs),such as rosiglitazone(RSG),which activates peroxisome proliferator activated receptor-y(PPARy),are a potent class of oral antidiabetic agents with good durability.However,the clinical use of TZDs is challenging because of their side effects,including weight gain and hepatotoxicity.Here,we found that bavachinin(BVC),a lead natural product,additively activates PPARγ with lowdose RSG to preserve the maximum antidiabetic effects while reducing weight gain and hepatotoxicity in db/db mice caused by RSG monotherapy.Structural and biochemical assays demonstrated that an unexplored hotspot around Met329 and Ser332 in helix 5 is triggered by BVC cobinding to RSG-bound PPARy,thereby allosterically stabilizing the active state of the activation-function 2 motif responsible for additive activation with RSG.Based on this hotspot,we discovered a series of new classes of allosteric agonists inducing the activity of TZDs in the same manner as BVC.Together,our data illustrate that the hotspot of PPARγ is druggable for the discovery of new allosteric synergists,and the combination thera py of allosteric synergists and TZD drugs may provide a potential alternative approach to the treatment of type 2 diabetes mellitus.展开更多
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.
文摘In order to screen out effective fungicides for controlling citrus canker,the control effects of 9 fungicides on Jinhong bingtang orange canker were studied.The results showed that 77%cupric calcium sulfate WP,30%copper oxychloride SC,46%copper hydroxide WG,30%thiodiazole-copper SC and 40%zinc thiazole SC had better comprehensive control effect on citrus canker,6%benziothiazolinone WG had an average effect,3%zhongshengmycin AS,2%kasugamycin AS and 33.5%oxine-copper SC had poor control effect.Therefore,fungicides could be used alternately or choose compounded preparation.In addition,adjuvants could be considered in use,which was an effective way to enhance efficacy,reduced dosage and delayed pesticide resistance.
基金The authors are extremely grateful to the National Nature Science Foundation of China for supporting this research （No.20962018, No20862015, No.20762009 and No.20562011）.
文摘A series of novel pyrazoles compounds were synthesized by the reaction of five kinds of substitute α-bromoacetophenone with pyrazole intermediates which was prepared by the reaction of chalcones and thiosemicarbazones. This method has some advantages such as mild reaction condition, easy operation and higher yield. All the compounds were confirmed by elemental analysis, IR and 1H NMR.
基金the National Natural Science Foundation of China(21708025,81925034,91753117,and 81773793)the Open Fund of State Key Laboratory of Oncogenes and Related Genes,Shanghai Jiao Tong University School of Medicine+3 种基金the Innovation Program of Shanghai Municipal Education Commission(2019-01-07-00-01-E00036)the Shanghai Science and Technology Innovation Foundation(19431901600)the China Postdoctoral Science Foundation(2016M601618 and 2017T100303)the National Science and Technology Major Project of China(2018ZX09711001-005-022)。
文摘Thiazolidinediones(TZDs),such as rosiglitazone(RSG),which activates peroxisome proliferator activated receptor-y(PPARy),are a potent class of oral antidiabetic agents with good durability.However,the clinical use of TZDs is challenging because of their side effects,including weight gain and hepatotoxicity.Here,we found that bavachinin(BVC),a lead natural product,additively activates PPARγ with lowdose RSG to preserve the maximum antidiabetic effects while reducing weight gain and hepatotoxicity in db/db mice caused by RSG monotherapy.Structural and biochemical assays demonstrated that an unexplored hotspot around Met329 and Ser332 in helix 5 is triggered by BVC cobinding to RSG-bound PPARy,thereby allosterically stabilizing the active state of the activation-function 2 motif responsible for additive activation with RSG.Based on this hotspot,we discovered a series of new classes of allosteric agonists inducing the activity of TZDs in the same manner as BVC.Together,our data illustrate that the hotspot of PPARγ is druggable for the discovery of new allosteric synergists,and the combination thera py of allosteric synergists and TZD drugs may provide a potential alternative approach to the treatment of type 2 diabetes mellitus.
