Xiaohui Li

Dalian University of Technology, Dalian, Liaoning, China

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Publications (9)21.08 Total impact

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    ABSTRACT: The histone deacetylase (HDAC) family is a promising drug target class owing to the importance of these enzymes in a variety of cellular processes. Docking studies were conducted to identify novel HDAC inhibitors. Subtle modifications in the recognition domain were introduced into a series of chlamydocin analogues, and the resulting scaffolds were combined with various zinc binding domains. Remarkably, cyclo(L-Asu(NHOH)-L-A3mc6c-L-Phe-D-Pro, compound 1 b), with a methyl group at positions 3 or 5 on the aliphatic ring, exhibited better antiproliferative effects than trichostatin A (TSA) against MCF-7 and K562 cell lines. In addition to cell-cycle arrest and apoptosis, cell migration inhibition was observed in cells treated with compound 1 b. Subsequent western blot analysis revealed that the balance between matrix metalloproteinase 2 (MMP2) and tissue inhibitors of metalloproteinase 1 (TIMP1) determines the degree of metalloproteinase activity in MCF-7 cells, thereby regulating cell migration. The improved inhibitory activity imparted by altering the hydrophobic substitution pattern at the bulky cap group is a valuable approach in the development of novel HDAC inhibitors.
    ChemMedChem 11/2013; · 2.84 Impact Factor
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    ABSTRACT: Histone deacetylases inhibitors (HDACIs) have become an attractive class of anticancer agents. In order to find some novel potent HDACIs, we designed and synthesized a series of l-2-benzyloxycarbonylamino-8-(2-pyridyl)-disulfidyloctanoic acid derivatives. All compounds exhibited potent HDAC-inhibitory activity, and two of them had similar potency to TSA. The introduction of 2-amino-4-phenylthiazole or 9-methyleneoxy-fluorenyl group at the surface recognize domain of these HDACIs could greatly increase their HDAC-inhibitory activity. Molecular modeling studies indicated that coordination of the zinc ion by these inhibitors, and formation of hydrogen bond and hydrophobic interaction between inhibitors and HDACs were essential for the HDAC-inhibitory activities of these inhibitors. Asp181, Asp269, Leu276 and Tyr308 in the active site of HDAC2 gave favorable contributions for binding with all compounds.
    European journal of medicinal chemistry 03/2012; 52:111-22. · 3.27 Impact Factor
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    ABSTRACT: Histone deacetylase inhibitors (HDACIs) are a promising class of anticancer agents. To examine whether a slight change in the recognition domain could alter their inhibitory activity, we synthesized a series of cyclo(-L-Am7(S2Py)-Aib-L-Phe(n-Me)-D-Pro)derivatives and evaluated their HDAC inhibitory and anticancer activities. The peptides exhibited potent HDAC inhibitory activity and inhibited three human cancer cell lines with IC₅₀ in the micromolar range. Docking and molecular dynamics simulation were conducted to explore the interaction mechanisms of class I and II HDACs with these inhibitors. It revealed that the zinc ion in the active site coordinated five atoms of HDACs and the sulfur atom of the inhibitor. The metal binding domains of these compounds interacted with HDAC2, and the surface recognition domains of these compounds interacted with HDAC4 through hydrogen bonding. The hydrophobic interactions also provided favorable contributions to stabilize the complexes. The results obtained from this study would be helpful for us to design some novel cyclic tetrapeptides that may act as potent HDACIs.
    Journal of Peptide Science 01/2012; 18(4):242-51. · 2.07 Impact Factor
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    ABSTRACT: Spraying and spraying with an electrostatic field (SEF) were employed to prepare alginate microspheres for delivering proteins, especially for intestinal digestive enzymes and cytokines. The encapsulation efficiency (EE) of a model protein [bovine serum albumin (BSA)] at a pH value lower than the isoelectric point was 20% higher than that at a natural pH. Moreover, for the microspheres prepared by SEF, EE improved significantly with increasing electric voltage. The interactions between BSA and the alginate microspheres were identified with Fourier transform infrared spectroscopy. The release profiles in vitro showed a controlled and pH-responsive release manner for the encapsulated BSA. A first-order release equation was postulated and modified to describe the release kinetics with an obviously initial burst release related to the eroded porous matrix. The equation fit the release data well when the pH value and composition of the release media were changed. The analysis of the release kinetics indicated that the drug release rate was in an inverse ratio to the diameter of the microspheres. Increasing the gas flow rate or electric voltage decreased both the mean diameter and size distribution of the microspheres significantly and enhanced the release rate of loaded drugs from alginate microspheres. Sodium dodecyl sulfate/polyacrylamide gel electrophoresis analysis revealed that BSA kept its structural integrity during the encapsulation and release process. © 2008 Wiley Periodicals, Inc. J Appl Polym Sci, 2008
    Journal of Applied Polymer Science 08/2008; 110(4):2488 - 2497. · 1.40 Impact Factor
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    ABSTRACT: Histone deacetylases (HDACs) play an important role in gene transcription, and inhibitors of HDACs can induce cell differentiation and suppress cell proliferation in tumor cells. Histone deacetylase1 (HDAC1) binds suberanilohydroxamic acid (SAHA) and 7-phenyl-2, 4, 6-hepta-trienoyl hydroxamic acid (CG-1521) with moderately low affinity (DeltaG = -8.6 and -7.8 kcal mol(-1)). The structurally related (E)-2-(3-(3-(hydroxyamino)-3-oxoprop-1-enyl)phenyl)-N(1),N(3)-diphenylmalonamide (SK-683), a Trichostatin A (TSA)-like HDAC1 inhibitor, and TSA are bound to the HDAC1 with -12.3 and -10.3 kcal mol(-1) of DeltaG, higher binding free energies than SAHA and CG-1521. Histone deacetylase-like protein (HDLP), an HDAC homologue, shows a 35.2% sequence identity of HDLP and human HDAC1. Molecular dynamics simulation and the molecular mechanics/generalized-Born surface area (MM-GBSA) free energy calculations were applied to investigate the factors responsible for the relatively activity of these four inhibitors to HDLP. In addition, computational alanine scanning of the binding site residues was carried out to determine the contribution components from van der Waals, electrostatic interaction, nonpolar and polar energy of solvation as well as the effects of backbones and side-chains with the MM-GBSA method. MM-GBSA methods reproduced the experimental relative affinities of the four inhibitors in good agreement (R(2) = 0.996) between experimental and computed binding energies. The MM-GBSA calculations showed that, the number of hydrogen bonds formed between the HDLP and inhibitors, which varied in the system studied, and electrostatic interactions determined the magnitude of the free energies for HDLP-inhibitor interactions. The MM-GBSA calculations revealed that the binding of HDLP to these four hydroxamic acid inhibitors is mainly driven by van der Waals/nonpolar interactions. This study can be a guide for the optimization of HDAC inhibitors and future design of new therapeutic agents for the treatment of cancer.
    Proteins Structure Function and Bioinformatics 05/2008; 73(1):134-49. · 3.34 Impact Factor
  • Xiaoqing Liu, Zhilong Xiu, Xiaohui Li
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    ABSTRACT: Many classes of functional cyclic peptide molecules are determined by experimental techniques, but few similarities of cyclic peptides are detectable. We propose three numerical characterizations of conformations of cyclic peptides. By incorporating the information on atomic coordinates of cyclic peptides, the coordinates are transformed into a characteristic sequence. Then we calculate its center of gravity, the eigenvalues of its Euclidean and L/L matrices, and regard them as descriptors to numerically characterize the conformations of cyclic peptides. Finally, the method is tested by analyzing the similarities of cyclic peptides presented in Table 1.
    Journal of Computational Chemistry 01/2008; 28(16):2545-51. · 3.84 Impact Factor
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    ABSTRACT: The inclusion interaction between quercetin and β-cyclodextrin (β-CD) binding site has been investigated, based on PM3 and ONIOM2 methods. The obtained results clearly indicate that the orientation in which the B ring of the guest molecule located near the secondary hydroxyls of the β-CD cavity is preferred in the binding energy. Moreover, Analyses regarding the complex structures suggest that one hydrogen bond between 7-hydroxy group (OH) of quercetin and 6-OH of β-CD is formed. This hydrogen bond interaction plays an important role in the bound quercetin/β-CD complex.
    Journal of Inclusion Phenomena 07/2007; 58(3):337-344. · 1.40 Impact Factor
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    ABSTRACT: In order to produce functional microspheres with different ranges of sizes for various applications, the size of alginate droplets prepared by dropping and spraying was studied. It was shown that the mean diameter could be controlled by liquid flow velocity and applied voltage as operating parameters using a conventional dropping and an electrostatic dropping method, separately. The formation mechanism of alginate droplets could be categorized into two different modes: Dripping mode and jetting mode. By employing an effective force analysis, the diameters in each modes showed to be well agreed with the numerical simulation within 7% deviations. It was testified that the initial amount of surface charges had a high impact on droplet diameter and the liquid flow velocity played a more important role on mean diameter of alginate droplets by electrostatic dropping method in dripping mode than in jetting mode. Then, an empirical equation and a semi-empirical model were used to simulate the diameter of droplets obtained by spraying and spraying with electrostatic field (SEF) method, respectively. The decrease in diameter was more sensitive to the increase of gas flow rate than to the decrease of liquid flow rate, and the results of two models fitted well with experimental values. The simulations showed that SEF yielded a 20% lower on droplet diameter than simple spraying method.
    Journal of Microencapsulation 07/2007; 24(4):303-22. · 1.57 Impact Factor
  • Source
    Chunli Yan, Xiaohui Li, Zhilong Xiu, Ce Hao
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    ABSTRACT: The inclusion process involving β-cyclodextrin (β-CD) and quercetin has been investigated by using the PM3 quantum-mechanical semi-empirical method. In the β-CD quercetin inclusion complex, a large portion of the flavonoid skeleton is included in the β-CD cavity and the bond connected ring B with ring C is inclined to the molecular axis of β-CD. The orientation in which the B ring of the guest molecule located near the secondary hydroxyls of the β-CD cavity is preferred in energy. One intermolecular hydrogen bond is formed. The molecular modeling results are in agreement with the NMR observations and molecular dynamics (MD) simulations. The statistical thermodynamic calculations at 1 atm and 298.15 K by PM3 demonstrate that 1:1 quercetin/β-CD complex is favored by a negative enthalpy change.
    Journal of Molecular Structure THEOCHEM 01/2006; 764:95-100. · 1.37 Impact Factor