Protoporphyrinogen oxidase （PPO, EC 1.3.3.4） is one of the most significant targets for a large family of in- hibitors that may be used as herbicide, bactericide, fungicide, or photosensitizing activator to treat ca...Protoporphyrinogen oxidase （PPO, EC 1.3.3.4） is one of the most significant targets for a large family of in- hibitors that may be used as herbicide, bactericide, fungicide, or photosensitizing activator to treat cancer through photodynamic therapy （PDT）. Molecular docking and CoMFA were combined in a multistep framework with the ultimate goal of identifying important factor contributing to the activity of PPO inhibitors. As a continuation of the previous research work on the development of new PPO inhibitors, the bioassay results indicated that good PPO in- hibitors were discovered in all of the three chemical series with ICs0 values ranging from 0.010 to 0.061 pmol·L ^-1. Using the crystal structure of tobacco mitochondrial PPO （mtPPO） as template, all the compounds were docked into the enzyme active site. The docking pose of each compound was subsequently used in a receptor-based alignment, leading to the development of a significant CoMFA model with r^2 value of 0.98 and q^2 （cross validation r^2） value of 0.63. This novel multistep framework gives insight into the and it can be extended to other classes of PPO inhibitors. In be particularly applicable in virtual screening procedures. structural characteristics for the binding of inhibitors, addition, the simplicity of the proposed approach may展开更多
It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approve...It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors by carrying out structural modifications and optimizations in future studies.展开更多
Mn（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cu（Ⅱ）, Pd（Ⅱ） and Ru（Ⅲ） complexes of Schiff bases derived from the condensation of sulfaguanidine with 2,4-dihydroxy benzaldehyde （HL1）, 2-hydroxy-l-naphthaldehyde （HL2） and ...Mn（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cu（Ⅱ）, Pd（Ⅱ） and Ru（Ⅲ） complexes of Schiff bases derived from the condensation of sulfaguanidine with 2,4-dihydroxy benzaldehyde （HL1）, 2-hydroxy-l-naphthaldehyde （HL2） and salicylaldehyde （HL3） have been synthesized. The structures of the prepared metal complexes were proposed based on elemental analysis, molar conductance, thermal analysis （TGA, DSC and DTG）, magnetic susceptibility measurements and spectroscopic techniques （IR, UV-Vis, and ESR）. In all complexes, the ligand bonds to the metal ion through the azomethine nitrogen and a-hydroxy oxygen atoms. The structures of Pd（Ⅱ） complex 8 and Ru（Ⅲ） complex 9 were found to be polynuclear. Two kinds of stereochemical geometries; distorted tetrahedral and distorted square py- ramidal, have been realized for the Cu（Ⅱ） complexes based on the results of UV-Vis, magnetic susceptibility and ESR spectra whereas octahedral geometry was predicted for Co（Ⅱ）, Mn（Ⅱ） and Ru（Ⅲ） complexes. Ni（Ⅱ） com- plexes were predicted to be square planar and tetrahedral and Pd（Ⅱ） complexes were found to be square planar. The antimicrobial activity of the ligands and their metal complexes was also investigated against the gram-positive bac- teria Staphylococcus aures and Bacillus subtilis and gram-negative bacteria, Escherichia coli and Pesudomonas aeruginosa, by using the agar dilution method. Chloramphenicol was used as standard compound. The obtained data revealed that the metal complexes are more or less, active than the parent ligand and standard. The X-ray crys- tal structure of HL3 has been also reported.展开更多
文摘Protoporphyrinogen oxidase （PPO, EC 1.3.3.4） is one of the most significant targets for a large family of in- hibitors that may be used as herbicide, bactericide, fungicide, or photosensitizing activator to treat cancer through photodynamic therapy （PDT）. Molecular docking and CoMFA were combined in a multistep framework with the ultimate goal of identifying important factor contributing to the activity of PPO inhibitors. As a continuation of the previous research work on the development of new PPO inhibitors, the bioassay results indicated that good PPO in- hibitors were discovered in all of the three chemical series with ICs0 values ranging from 0.010 to 0.061 pmol·L ^-1. Using the crystal structure of tobacco mitochondrial PPO （mtPPO） as template, all the compounds were docked into the enzyme active site. The docking pose of each compound was subsequently used in a receptor-based alignment, leading to the development of a significant CoMFA model with r^2 value of 0.98 and q^2 （cross validation r^2） value of 0.63. This novel multistep framework gives insight into the and it can be extended to other classes of PPO inhibitors. In be particularly applicable in virtual screening procedures. structural characteristics for the binding of inhibitors, addition, the simplicity of the proposed approach may
文摘It has been widely known that human epidermal growth factor receptor 2 (HER2) inhibitors exhibit distinct antitumor responses against HER2-positive breast cancer. To date, Lapatinib (Tykerb®) has been approved by the U.S. Food and Drug Administration (FDA) as a reversible HER2 inhibitor for treating breast cancer. However, HER2 L755S, T798I and T798M mutations confer drug resistance to lapatinib, restricting its efficacy toward HER2-positive breast cancer. Thus, novel therapy toward mutant HER2 is highly desired. Although several irreversible HER2 inhibitors have been developed to overcome these drug resistance problems, most of them were reported to cause severe side effects. In this study, three pharmacophore models based on HER2 L755S, T798I and T798M mutant structures were constructed and then validated through receiver operating characteristic (ROC) curve analysis and Güner-Henry (GH) scoring methods. Subsequently, these well-validated models were utilized as 3D queries to identify novel irreversible HER2 inhibitors from National Cancer Institute (NCI) database. Finally, two potential irreversible HER2 inhibitor candidates, NSC278329 and NSC718305, were identified and validated through molecular docking, molecular dynamics (MD) simulations and ADMET prediction. Furthermore, the analyses of binding modes showed that both NSC278329 and NSC718305 exhibit good binding interactions with HER2 L755S, T798I and T798M mutants. All together, the above results suggest that both NSC278329 and NSC718305 can serve as novel and effective irreversible HER2 inhibitors for treating breast cancers with HER2 L755S, T798I and T798M mutants. In addition, they may act as lead compounds for designing new irreversible HER2 inhibitors by carrying out structural modifications and optimizations in future studies.
文摘Mn（Ⅱ）, Co（Ⅱ）, Ni（Ⅱ）, Cu（Ⅱ）, Pd（Ⅱ） and Ru（Ⅲ） complexes of Schiff bases derived from the condensation of sulfaguanidine with 2,4-dihydroxy benzaldehyde （HL1）, 2-hydroxy-l-naphthaldehyde （HL2） and salicylaldehyde （HL3） have been synthesized. The structures of the prepared metal complexes were proposed based on elemental analysis, molar conductance, thermal analysis （TGA, DSC and DTG）, magnetic susceptibility measurements and spectroscopic techniques （IR, UV-Vis, and ESR）. In all complexes, the ligand bonds to the metal ion through the azomethine nitrogen and a-hydroxy oxygen atoms. The structures of Pd（Ⅱ） complex 8 and Ru（Ⅲ） complex 9 were found to be polynuclear. Two kinds of stereochemical geometries; distorted tetrahedral and distorted square py- ramidal, have been realized for the Cu（Ⅱ） complexes based on the results of UV-Vis, magnetic susceptibility and ESR spectra whereas octahedral geometry was predicted for Co（Ⅱ）, Mn（Ⅱ） and Ru（Ⅲ） complexes. Ni（Ⅱ） com- plexes were predicted to be square planar and tetrahedral and Pd（Ⅱ） complexes were found to be square planar. The antimicrobial activity of the ligands and their metal complexes was also investigated against the gram-positive bac- teria Staphylococcus aures and Bacillus subtilis and gram-negative bacteria, Escherichia coli and Pesudomonas aeruginosa, by using the agar dilution method. Chloramphenicol was used as standard compound. The obtained data revealed that the metal complexes are more or less, active than the parent ligand and standard. The X-ray crys- tal structure of HL3 has been also reported.
