Zhengguang Zhu

Southern Medical University, Shengcheng, Guangdong, China

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Publications (5)10.73 Total impact

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    ABSTRACT: Vascular endothelial growth factors receptor-2 (VEGFR-2) inhibitors have been proved as very effective anticancer agents. Structurally similar ligands 1 and 2 show almost the same inhibitory activities against VEGFR-2, but they bind to the enzyme in distinct binding mode. Ligand 1 targets DFG-in active conformation of VEGFR-2, known as Type I inhibitor. On the other hand, ligand 2 targets DFG-out inactive conformation of VEGFR-2, known as Type II inhibitor or allosteric kinase inhibitor. Ligand 2 shows high inhibitory activity, while the compound 3, a close analog of 2 with the cyclopropylamide replaced by tert-butylamide, exhibits drastically diminished potency. In this work, molecular dynamics simulations and free energy calculations were performed on inhibitors 1-3 binding to active and inactive conformation of VEGFR-2. Molecular dynamics simulations find that the active conformation binding to Type I inhibitor 1 appears more flexible when compared to the unbound form. In contrast, binding of Type II inhibitor 2 to the inactive conformation helps to stabilize the inactive conformation of the protein. Binding free energy calculations verify that inhibitor 1 and 2 have almost the same activities against VEGFR-2, and that ligand 1 binds to and stabilizes the DFG-in conformation of VEGFR-2, which is in agree with the experimental observation. Molecular dynamics simulations and binding free energy calculations of 3 binding to VEGFR-2 can give a good explanation of the drastically diminished potency. Free energy analysis revealed that van der Waals interactions provided the substantial driving force for the binding process. The important hydrophobic property of the terminal 4-Cl phenyl was required to be type II inhibitors. Furthermore, per-residue free energy decomposition analysis revealed that the most favorable contribution came from Leu840, Val848, Ala866, Lys868, Leu889, Val899, Thr916, Phe918, Cys919, Leu1035, Cys1045, Asp1046, and Phe1047. These results are expected to be useful for future rational design of novel potent VEGFR-2 inhibitors.
    No preview · Article · Dec 2014 · Journal of Molecular Graphics and Modelling
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    ABSTRACT: Deregulation of receptor tyrosine kinase c-Met has been reported in human cancers and is considered as an attractive target for small molecule drug discovery. In this study, a series of spiro[indoline-3, 4'-piperidine]-2-ones were designed, synthesized and evaluated as novel c-Met inhibitors. The results showed that the majority of the compounds exhibited significant inhibitory effect on c-Met with IC(50) values of 0.0147-17 μM in TR-FRET-based assay and IC(50) values of 1.56-1400 μM in cell-based assay. Furthermore, our docking experiments verified the results and explained the molecular mechanism of eminent activities to c-Met.
    No preview · Article · Feb 2012 · European Journal of Medicinal Chemistry
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    ABSTRACT: Tie-2, a kind of endothelial cell tyrosine kinase receptor, is required for embryonic blood vessel development and tumor angiogenesis. Several compounds that showed potent activity toward this attractive anticancer drug target in the assay have been reported. In order to investigate the structure-activity correlation of indolocarbazole series compounds and modify them to improve their selectivity and activity, 3D-QSAR models were built using CoMFA and CoMSIA methods and molecular docking was used to check the results. Based on the common sketch align, two good QSAR models with high predictabilities (CoMFA model: q(2) = 0.823, r(2) = 0.979; CoMSIA model: q(2) = 0.804, r(2) = 0.967) were obtained and the contour maps obtained from both models were applied to identify the influence on the biological activity. Molecular docking was then used to confirm the results. Combined with the molecular docking results, the detail binding mode between the ligands and Tie-2 was elucidated, which enabled us to interpret the structure-activity relationship. These satisf actory results not only offered help to comprehend the action mechanism of indolocarbazole series compounds, but also provide new information for the design of new potent inhibitors.
    Full-text · Article · Dec 2011 · International Journal of Molecular Sciences
  • Shaoyu Wu · Zhiqin Li · Jiajie Zhang · Wei Xu · Zhengguang Zhu · Chuanlin Yu · Shuguang Wu
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    ABSTRACT: This is the first report to purify a new peptide SV-PP-1 from Agkistrodon blomhoffii Bioe. SV-PP-1 has molecular weight of 1234.616 Da and can inhibit on platelet aggregation. SV-PP-1 significantly inhibited the ADP-induced platelet aggregation. It has been found up to now that SV-PP-1 is the smallest peptide inhibiting on platelet aggregation from snake venom.
    No preview · Article · Dec 2004 · Zhong yao cai = Zhongyaocai = Journal of Chinese medicinal materials
  • Shuwen Liu · Shibo Jiang · Zhihua Wu · Lin Lv · Jiajie Zhang · Zhengguang Zhu · Shuguang Wu
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    ABSTRACT: An increasing portion of patients with HIV infection and/or AIDS cannot use currently FDA-approved anti-HIV drugs, including the reverse transcriptase and protease inhibitors, due to the adverse effects and the emergence of drug resistance. Thus, it is essential to develop new anti-HIV agents with a target different from the HIV reverse transcriptase and protease. Using a conformation-specific monoclonal antibody NC-1, we previously established a high throughput screening assay for identification of small molecular organic compounds that disrupt the HIV-1 gp41 six-helix bundle formation, a critical step of membrane fusion between the HIV and the target cell. In the present study, we used this assay to screen for inhibitors of the gp41 six-helix bundle formation from aqueous extracts of nine Chinese medicinal herbs with antiviral activity. We found that the extracts of two herbs, Prunella vulgaris and Rhizoma cibotte, showed potent inhibitory activity. The inhibitory activity of these two herb extracts significantly decreased after they were passed through polyamide resin mini-columns, which are able to bind polyphenols including tannin, an HIV-1 inhibitor with multiple mechanisms of action. The bound polyphenols were eluted from the polyamide columns and also showed potent inhibitory activity on the gp41 six-helix bundle formation. Tannin purchased from different commercial sources inhibited the gp41 six-helix bundle formation in a manner similar to the polyphenols isolated from the herb extracts. These results suggest that tannin may be one of major inhibitors of the HIV-1 gp41 six-helix bundle formation in the herb extracts and that tannin may inhibit HIV-1 entry by disrupting the gp41 six-helix bundle formation.
    No preview · Article · Sep 2002 · Life Sciences