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Zhenshan Zhang

Bio: Zhenshan Zhang is an academic researcher from Chinese Academy of Sciences. The author has contributed to research in topics: Quantitative structure–activity relationship & Docking (molecular). The author has an hindex of 7, co-authored 8 publications receiving 166 citations.

Papers
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Journal ArticleDOI
TL;DR: The dipeptide H‐Trp‐Glu‐OH (G3335) was discovered to be a novel PPARγ antagonist and the results suggested that residues Cys285, Arg288, Ser289, and His449 in PParγ play vital roles inPPARγ‐LBD–G33 35 binding.
Abstract: The peroxisome proliferator-activated receptor gamma (PPARgamma) is an important therapeutic drug target for several conditions, including diabetes, inflammation, dyslipidemia, hypertension, and cancer. It is shown that an antagonist or partial agonist of PPARgamma has attractive potential applications in the discovery of novel antidiabetic agents that may retain efficacious insulin-sensitizing properties and minimize potential side effects. In this work, the dipeptide H-Trp-Glu-OH (G3335) was discovered to be a novel PPARgamma antagonist. Biacore 3000 results based on the surface plasmon resonance (SPR) technique showed that G3335 exhibits a highly specific binding affinity against PPARgamma (K(D) = 8.34 microM) and is able to block rosiglitazone, a potent PPARgamma agonist, in the stimulation of the interaction between the PPARgamma ligand-binding domain (LBD) and RXRalpha-LBD. Yeast two-hybrid assays demonstrated that G3335 exhibits strong antagonistic activity (IC50 = 8.67 microM) in perturbing rosiglitazone in the promotion of the PPARgamma-LBD-CBP interaction. Moreover, in transactivation assays, G3335 was further confirmed as an antagonist of PPARgamma in that G3335 could competitively bind to PPARgamma against 0.1 microM rosiglitazone to repress reporter-gene expression with an IC50 value of 31.9 muM. In addition, homology modeling and molecular-docking analyses were performed to investigate the binding mode of PPARgamma-LBD with G3335 at the atomic level. The results suggested that residues Cys285, Arg288, Ser289, and His449 in PPARgamma play vital roles in PPARgamma-LBD-G3335 binding. The significance of Cys285 for PPARgamma-LBD-G3335 interaction was further demonstrated by PPARgamma point mutation (PPARgamma-LBD-Cys285Ala). It is hoped our current work will provide a powerful approach for the discovery of PPARgamma antagonists, and that G3335 might be developed as a possible lead compound in diabetes research.

43 citations

Journal ArticleDOI
TL;DR: The surface plasmon resonance biosensor results showed that the equilibrium dissociation constant (KD) values evaluated by Biacore 3000 for the inhibitors showed a good correlation with its reported IC50, suggesting that SPR technology might be applicable as a direct assay method in screening new 5-LOX inhibitors at an early stage.
Abstract: The binding features of a series of 5-lipoxygenase (5-LOX) inhibitors (caffeic acid, NDGA, AA-861, CDC, esculetin, gossypol and phenidone) to human 5-LOX have been studied by using surface plasmon resonance biosensor (SPR) technology based Biacore 3000 and molecular docking simulation analyses. The SPR results showed that the equilibrium dissociation constant (KD) values evaluated by Biacore 3000 for the inhibitors showed a good correlation with its reported IC50, suggesting that SPR technology might be applicable as a direct assay method in screening new 5-LOX inhibitors at an early stage. In addition, the 3D structural model of 5-LOX was generated according to the crystal structure of rabbit reticulocyte 15-lipoxygenase, and the molecular docking simulation analyses revealed that the predicted binding free energies for the inhibitors correlated well with the KD values measured by SPR assay, which implies the correctness of the constructed 3D structural model of 5-LOX. This current work has potential for application in structure-based 5-LOX inhibitor discovery.

35 citations

Journal ArticleDOI
TL;DR: Both the docking simulations and QSAR analyses suggest that new potent dual inhibitors should share a structural feature with a moderately bulky group at R2 position and a rather negatively charged group around the position of the carbonyl group of DHDMBFs.

24 citations

Journal ArticleDOI
TL;DR: The CoMFA model indicated that bulky negative-charged group at position 9, 10 and 11 of CPT would increase activity, but excessively increasing bulky group at Position 10 is adverse to inhibitory activity; substituents that occupy position 7 with the bulky positive group will enhance the inhibitive activity.
Abstract: To build up a quantitative structure-activity relationship (QSAR) model of 20 (S)-camptothecin (CPT) analogs for the prediction of the activity of new CPT analogs for drug design. A training set of 43 structurally diverse CPT analogs which were inhibitors of topoisomerase I were used to construct a quantitative structure–activity relationship model with a comparative molecular field analysis (CoMFA). The QSAR model was optimized using partial least squares (PLS) analysis. A test set of 10 compounds was evaluated using the model. The CoMFA model was constructed successfully, and a good cross-validated correlation was obtained in which q2 was 0.495. Then, the analysis of the non-cross-validated PLS model in which r2 was 0.935 was built and permitted demonstrations of high predictability for the activities of the 10 CPT analogs in the test set selected in random. The CoMFA model indicated that bulky negative-charged group at position 9, 10 and 11 of CPT would increase activity, but excessively increasing bulky group at position 10 is adverse to inhibitory activity; substituents that occupy position 7 with the bulky positive group will enhance the inhibitive activity. The model can be used to design new CPT analogs and understand the mechanism of action.

21 citations

Journal ArticleDOI
TL;DR: In this paper, a series of indole-2-carboxamide compounds with human liver glycogen phosphorylase a (HLGPa) have been studied employing molecular docking and 3D-QSAR approaches.

19 citations


Cited by
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TL;DR: In this overview, 13 papers that should be on everyone's ‘must read’ list for 2003 are spotlighted and examples of how to identify and interpret high‐quality biosensor data are provided.
Abstract: In the year 2003 there was a 17% increase in the number of publications citing work performed using optical biosensor technology compared with the previous year. We collated the 962 total papers for 2003, identified the geographical regions where the work was performed, highlighted the instrument types on which it was carried out, and segregated the papers by biological system. In this overview, we spotlight 13 papers that should be on everyone's 'must read' list for 2003 and provide examples of how to identify and interpret high-quality biosensor data. Although we still find that the literature is replete with poorly performed experiments, over-interpreted results and a general lack of understanding of data analysis, we are optimistic that these shortcomings will be addressed as biosensor technology continues to mature.

518 citations

Journal ArticleDOI
TL;DR: Structural features of PPAR receptors are summarized, the method ofPPAR modulator design is illustrated, and recent dual- and pan-agonist with different therapeutic outcomes of the receptor are analyzed to be used as a target for drugs in future.

244 citations

Journal ArticleDOI
Longhuo Wu1, Xiao Wang, William Xu, Farzin Farzaneh, Ruian Xu 
TL;DR: This review will focus on recent advances in molecular and cellular mechanisms of coumarin action involved with the relationship between structure and activity.
Abstract: Coumarins are of many different structures. They constitute an important class of pharmacological agents possessing a range of different physiological activities including anti-cancer, anti-oxidant, anti- inflammation, anti-HIV, anti-coagulant, anti-bacterial, analgesic and comparative immune-modulation. Recently, coumarins have attracted intense research interest. Of great interest is the possibility that this class of molecules could be a source of drugs for the therapy of several diseases. These include recent insights into inhibiting cell proliferation by interfering with mitotic spindle microtubule function, decrease Matrix Metalloproteinase (MMP) activity, block the cell cycle in the S or G2/M phases to interfere with processes of cell division, suppress O2(-) generation in leukocytes, inhibit different protein kinases, modulate the signalings, induce carcinogen-detoxifying enzymes glutathione S-transferases (GSTs) and/or NAD(P)H quinine oxidoreductase (NQO1), suppress the phosphorylation of Akt/PKB as a mechanism inhibiting inflammation, progress in structure modification to increase in anti-fungal action, to broaden against bacteria spectrum, to enhance inhibiting activities of nitric oxide synthase (NOS) and cyclooxygenase (COX), to strengthen anti-oxidant activity and to exhibite a much higher cytotoxicity against human umbilical vein endothelial cell (HUVEC). With fewer non-hemorrhagic side effects than the indanedione derivatives, they can be applied as an oral anticoagulant commonly for preventing venous thromboembolism following orthopedic surgery, recurrent myocardial infarction and the treatment of systemic embolism in atrial fibrillation, together with the significant advances in the basis of drug action. It is therefore useful to build up some correlations with the data available in order to better explore the molecular and cellular mechanism of coumarin action in the treatment of diseases. This review will focus on recent advances in molecular and cellular mechanisms of coumarin action involved with the relationship between structure and activity.

217 citations

Journal ArticleDOI
TL;DR: The data implicate that AMPK is a key regulator of both AD-related pathways, and direct stimulation of AMPK with the cell-permeable activator, 5-aminoimidazole-4-carboxyamide ribonucleoside, replicated leptin's effects and conversely, Compound C, an inhibitor of AM PK, blocked leptin's action.

175 citations

Journal ArticleDOI
TL;DR: This review covers two decades of research and development for various NN RTI families based on their chemical scaffolds, and describes the structural similarity of NNRTIs.
Abstract: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent very potent and most promising anti-AIDS agents that specifically target the HIV-1 reverse transcriptase (RT). However, the effectiveness of NNRTI drugs can be hampered by rapid emergence of drug-resistant viruses and severe side effects upon long-term use. Therefore, there is an urgent need to develop novel, highly potent NNRTIs with broad spectrum antiviral activity and improved pharmacokinetic properties, and more efficient strategies that facilitate and shorten the drug discovery process would be extremely beneficial. Fortunately, the structural diversity of NNRTIs provided a wide space for novel lead discovery, and the pharmacophore similarity of NNRTIs gave valuable hints for lead discovery and optimization. More importantly, with the continued efforts in the development of computational tools and increased crystallographic information on RT/NNRTI complexes, structure-based approaches using a combination of traditional medicinal chemistry, structural biology, and computational chemistry are being used increasingly in the design of NNRTIs. First, this review covers two decades of research and development for various NNRTI families based on their chemical scaffolds, and then describes the structural similarity of NNRTIs. We have attempted to assemble a comprehensive overview of the general approaches in NNRTI lead discovery and optimization reported in the literature during the last decade. The successful applications of medicinal chemistry strategies, crystallography, and computational tools for designing novel NNRTIs are highlighted. Future directions for research are also outlined.

173 citations