Suzhou, China
Suzhou, China

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Cao F.,Nanjing University | Li X.,Nanjing University | Ye L.,Suzhou NeuPharma Co. | Xie Y.,Nanjing University | And 6 more authors.
Environmental Toxicology and Pharmacology | Year: 2013

The binding interactions between hydroxylated polychlorinated biphenyls (HO-PCBs) and the aryl hydrocarbon receptor (AhR) are suspected of causing toxic effects. To understand the binding mode between HO-PCBs and AhR, and to explore the structural characteristics that influence the AhR agonistic activities of HO-PCBs, the combination of molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR), and molecular dynamics (MD) simulations was performed. Using molecular docking, the HO-PCBs were docked into the binding pocket of AhR, which was generated by homology modeling. Comparative molecular similarity index analysis (CoMSIA) models were subsequently developed from three different alignment rules. The optimum 3D-QSAR model showed good predictive ability (q2=0.583, R2=0.913) and good mechanism interpretability. The statistical reliability of the CoMSIA model was also validated. In addition, molecular docking and MD simulations were applied to explore the binding modes between the ligands and AhR. The results obtained from this study may lead to a better understanding of the interaction mechanism between HO-PCBs and AhR. © 2013 Elsevier B.V.


Li X.,Nanjing University | Ye L.,Suzhou NeuPharma Co. | Wang X.,Nanjing University | Shi W.,Nanjing University | And 4 more authors.
Archives of Environmental Contamination and Toxicology | Year: 2013

Endocrine-disrupting chemicals have attracted great concern. As major metabolites of polychlorinated biphenyls (PCBs), hydroxylated polychlorinated biphenyls (HO-PCBs) may disrupt estrogen hormone status because of their structural similarity to estrogen endogenous compounds. However, interactions between HO-PCBs and estrogen receptors (ERs) are not fully understood. In the present work, a molecular modeling study combining molecular docking, molecular dynamics simulations, and binding free energy calculations was performed to characterize the interactions of three HO-PCBs (40-HO-PCB50, 20-HO-PCB65, and 40-HO-PCB69) having much different estrogenic activities with ERβ. Docking results showed that binding between ligands and ERβ was stabilized by hydrogen bond and hydrophobic interactions. The binding free energies of three ligands with ERβ were calculated, and further binding free energy decomposition analysis indicated that the dominating driving force of the binding between the ligands and ERβ was the van der Waals interaction. Some key residues, such as Leu298, Phe356, Gly472, His475, and Leu476, played important roles in ligand-receptor interactions by forming hydrophobic and hydrogen bond interactions with ligands. The results may be beneficial to increase understanding of the interactions between HO-PCBs and ERβ. © Springer Science+Business Media New York 2013.


Li X.,Nanjing University | Ye L.,Suzhou NeuPharma Co. | Wang X.,Nanjing University | Shi W.,Nanjing University | And 5 more authors.
Chemosphere | Year: 2013

Polychlorinated biphenyls (PCBs) have attracted great concern as global environmental pollutants and representative endocrine disruptors. In this work, a molecular model study combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD) simulations was performed to explore the structural requirement for the anti-androgen activities of PCBs and to reveal the binding mode between the PCBs and androgen receptor (AR). The best comparative molecular similarity indices analysis (CoMSIA) model, obtained from receptor-based alignment, shows leave-one-out cross-validated correlation coefficient (q2) of 0.665 and conventional correlation coefficient (R2) of 0.945. The developed model has a highly predictive ability in both internal and external validation. Furthermore, the interaction mechanisms of PCBs to AR were analyzed by molecular docking and MD simulation. Molecular docking indicated that all the PCBs in the data set docked in a hydrophobic pocket. The Binding free energies calculated by Molecular mechanics-Poisson Boltzmann surface area (MM-PBSA) not only exhibited a good correlation with the experimental activity, but also could explain the activity difference of the studied compounds. The binding free energy decomposition analysis indicates that the van der Waals interaction is the major driving force for the binding process. © 2013 Elsevier Ltd.


Li X.,Nanjing University | Ye L.,Suzhou NeuPharma Co. | Wang X.,Nanjing University | Wang X.,Suzhou NeuPharma Co. | And 5 more authors.
Science of the Total Environment | Year: 2012

Hydroxylated polychlorinated biphenyls (HO-PCBs), major metabolites of PCBs, have been reported to present agonist or antagonist interactions with estrogen receptor α (ERα) and induce ER-mediated responses. In this work, a multistep framework combining molecular docking, molecular dynamics (MD) simulations, and structure-based three-dimensional quantitative structure-activity relationship (3D-QSAR) studies were performed to explore the influence of structural features on the estrogenic activities of HO-PCBs, and to investigate the molecular mechanism of ERα-ligand interactions. The CoMSIA (comparative molecular similarity indices analysis) model was developed from the conformations obtained from molecular docking. The model exhibited statistically significant results as the cross-validated correlation coefficient q2 was 0.648, the non-cross-validated correlation coefficient r2 was 0.968, and the external predictive correlation coefficient rpred 2 was 0.625. The key amino acid residues were identified by molecular docking, and the detailed binding modes of the compounds with different activities were determined by MD simulations. The binding free energies correlated well with the experimental activity. An energetic analysis, MM-GBSA energy decomposition, revealed that the van der Waals interaction was the major driving force for the binding of compounds to ERα. The hydrogen bond interactions between the ligands and residue His524 help to stabilize the conformation of ligands at the binding pocket. These results are expected to be beneficial to predict estrogenic activities of other HO-PCB congeners and helpful for understanding the binding mechanism of HO-PCBs and ERα. © 2012 Elsevier B.V.


Zhu Y.-L.,Suzhou NeuPharma Co. | Ye Z.-G.,Chinese Academy of Sciences
Chinese Journal of New Drugs | Year: 2011

Computational toxicology has been attracted great interests from both governmental agencies and research organizations. Its methods have been widely applied to predict drug toxicity and to assess environmental risks of chemicals. There are two categories of methods for chemical toxicity prediction, quantitative structure-activity relationship (QSAR) and molecular mechanism. Assessing toxicity of environmental chemicals has been developed in China; however, study on computational toxicity of chemical drugs has just started. Yet there has been no report on application of computational toxicology in traditional Chinese medicine (TCM). On the other hand, scientists outside of China have reported the predicting toxicities of natural products using commercial software or in-house QSAR models. Because chemical structures in TCM are more diversified and the chemical space is different from that of synthetic compounds and TCM is usually mixture of multiple chemical components, toxicity prediction of TCM is more challenging. Advances in "omics" technologies open new opportunities for computational toxicology of TCM.


Patent
Suzhou Neupharma Co. | Date: 2012-11-09

Chemical entities that are bufalin derivatives, pharmaceutical compositions and methods of treatment of cancer are described.


Disclosed are a composition comprising an beautyberry total glycosides extract, and a method of preparation thereof, and the use of the composition thereof in preparing drugs for treating neurodegenerative diseases or skin diseases. The extract thereof is prepared from the leaves of Callicarpa cathayana H.T. Chang or Callicarpa formosana Rolfe, and contains 18% to 45% verbascoside and 15% to 40% Arenarioside.


Patent
Suzhou Neupharma Co. | Date: 2016-06-20

Chemical entities that are bufalin derivatives, pharmaceutical compositions and methods of treatment of cancer are described.


Patent
Suzhou Neupharma Co. | Date: 2015-02-18

Chemical entities that are bufalin derivatives, pharmaceutical compositions and methods of treatment of cancer are described.


Disclosed is a composition comprising an beautyberry total glycosides extract, and a method of preparation thereof, and the use of the composition thereof in preparing drugs for treating neurodegenerative diseases or skin diseases. The extract thereof is prepared from the leaves of Callicarpa cathayana H. T. Chang or Callicarpa formosana Rolfe, and contains 18% to 45% verbascoside and 15% to 40% Arenarioside.

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