Jie Gui

Huazhong (Central China) Normal University, Wu-han-shih, Hubei, China

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Publications (3)7.06 Total impact

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    ABSTRACT: 3-Hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is a primary target in the current clinical treatment of hypercholesterolemia with specific inhibitors of "statin" family. Statins are excellent inhibitors of the class I (human) enzyme but relatively poor inhibitors of the class II enzyme, which are well-known as a potential target to discover drugs fighting against the invasive diseases originated from S. pneumoniae . However, no significantly effective inhibitors of class II HMGR have been reported so far. In the present study, the reasonable three-dimensional (3D) structure of class II HMGR from S. pneumoniae (SP-HMGR-II) was built by Swissmodel. On the basis of the modeling 3D structure in "close" flap domain form, several novel potential hit compounds out of SPECs database were picked out by using structure-based screening strategy. Especially the compounds 4, 3, and 11 exhibit highly inhibitory activities, with IC(50) values of 11.5, 18.5, and 18.1 μM, respectively. Furthermore, the hit compounds were chosen as probe molecules, and their probable interactions with the corresponding individual residues have been examined by jointly using the molecular docking, site-directed mutagenesis, enzymatic assays, and fluorescence spectra, to provide an insight into a new special binding-model located between the HMG-CoA and NADPH pockets. The good agreement between theoretical and experimental results indicate that the modeling strategies and screening processes in the present study are very likely to be a promising way to search novel lead compounds with both structural diversity and high inhibitory activity against SP-HMGR-II in the future.
    No preview · Article · Jun 2012 · Journal of Chemical Information and Modeling
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    ABSTRACT: 3-Hydroxy-3-methylglutaryl coenzyme A reductase (class II HMGR) could serve as a potential target to discover drugs fighting against the invasive diseases originated from Streptococcus pneumoniae, one of the major causes of bacterial disease in human. However, no strongly effective inhibitors of class II HMGR have been found so far. In the present study, for the first time, four annonaceous acetogenins (ACGs) were explored for the inhibition on S. pneumoniae HMGR. The results showed that the ACGs had higher inhibitory activities against S. pneumoniae HMGR with K(i) values in the range of 6.45-20.49 μM than the statin drug lovastatin (K(i)=116.25 μM), a classical inhibitor of class I HMGR. Then, three-dimensional modeling and docking simulations analyzed the possible binding mode of ACGs to S. pneumoniae HMGR and suggested a kind of novel structural and binding mode for designing promising inhibitor candidates of the targeted enzyme S. pneumoniae II HMGR.
    No preview · Article · Jun 2011 · Bioorganic & medicinal chemistry
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    ABSTRACT: Class II 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductases are potential targets for novel antibiotic development. In order to obtain a precise structural model for use in virtual screening and inhibitor design, HMG-CoA reductase of Streptococcus pneumoniae was cloned, overexpressed and purified to homogeneity using Ni-NTA affinity chromatography. Crystals were obtained using the hanging-drop vapour-diffusion method. A complete data set was collected from a single frozen crystal on a home X-ray source. The crystal diffracted to 2.3 Å resolution and belonged to the orthorhombic space group C222(1), with unit-cell parameters a = 773.4836, b = 90.3055, c = 160.5592 Å, α = β = γ = 90°. Assuming the presence of two molecules in the asymmetric unit, the solvent content was estimated to be 54.1% (V(M) = 2.68 Å(3) Da(-1)).
    Full-text · Article · Nov 2010 · Acta Crystallographica Section F Structural Biology and Crystallization Communications