Showing papers by "Kaixian Chen published in 2013"

Fluorogenic Probing of Specific Recognitions between Sugar Ligands and Glycoprotein Receptors on Cancer Cells by an Economic Graphene Nanocomposite

Abstract: Economical nanocomposites based on π-stacking of N-acetyl glycosyl rhodamine B to graphene oxide (GO) are simply prepared. These "sweet" GO-materials are proven to be admirable for the fluorogenic recognition of specific intercellular sugar-based ligand-glycoprotein receptor interactions of interest.

Capturing intercellular sugar-mediated ligand-receptor recognitions via a simple yet highly biospecific interfacial system

Abstract: Intercellular ligand-receptor recognitions are crucial natural interactions that initiate a number of biological and pathological events. We present here the simple construction of a unique class of biomimetic interfaces based on a graphene-mediated self-assembly of glycosyl anthraquinones to a screen-printed electrode for the detection of transmembrane glycoprotein receptors expressed on a hepatoma cell line. We show that an electroactive interface confined with densely clustered galactosyl ligands is able to ingeniously recognize the asialoglycoprotein receptors on live Hep-G2 cells employing simple electrochemical techniques. The only facility used is a personal laptop in connection with a cheap and portable electrochemical workstation.

Discovery and Mechanism Study of SIRT1 Activators that Promote the Deacetylation of Fluorophore-Labeled Substrate

Abstract: SIRT1 is an NAD(+)-dependent deacetylase, whose activators have potential therapeutic applications in age-related diseases. Here we report a new class of SIRT1 activators. The activation is dependent on the fluorophore labeled to the substrate. To elucidate the activation mechanism, we solved the crystal structure of SIRT3/ac-RHKK(ac)-AMC complex. The structure revealed that the fluorophore blocked the H-bond formation and created a cavity between the substrate and the Rossmann fold. We built the SIRT1/ac-RHKK(ac)-AMC complex model based on the crystal structure. K(m) and K(d) determinations demonstrated that the fluorophore decreased the peptide binding affinity. The binding modes of SIRT1 activators indicated that a portion of the activators interacts with the fluorophore through π-stacking, while the other portion inserts into the cavity or interacts with the Rossmann fold, thus increasing the substrate affinity. Our study provides new insights into the mechanism of SIRT1 activation and may aid the design of novel SIRT1 activators.

A knowledge-based halogen bonding scoring function for predicting protein-ligand interactions

Abstract: Halogen bonding, a non-covalent interaction between the halogen σ-hole and Lewis bases, could not be properly characterized by majority of current scoring functions In this study, a knowledge-based halogen bonding scoring function, termed XBPMF, was developed by an iterative method for predicting protein-ligand interactions Three sets of pairwise potentials were derived from two training sets of protein-ligand complexes from the Protein Data Bank It was found that two-dimensional pairwise potentials could characterize appropriately the distance and angle profiles of halogen bonding, which is superior to one-dimensional pairwise potentials With comparison to six widely used scoring functions, XBPMF was evaluated to have moderate power for predicting protein-ligand interactions in terms of “docking power”, “ranking power” and “scoring power” Especially, it has a rather satisfactory performance for the systems with typical halogen bonds To the best of our knowledge, XBPMF is the first halogen bonding scoring function that is not dependent on any dummy atom, and is practical for high-throughput virtual screening Therefore, this scoring function should be useful for the study and application of halogen bonding interactions like molecular docking and lead optimization

Inhibition of Human Neutrophil Elastase by Pentacyclic Triterpenes

Abstract: Scope Inhibiting human neutrophil elastase (HNE) is a promising strategy for treating inflammatory lung diseases, such as H1N1 and SARS virus infections. The use of sivelestat, the only clinically registered synthesized HNE inhibitor, is largely limited by its risk of organ toxicity because it irreversibly inhibits HNE. Therefore, potent reversible HNE inhibitors are promising alternatives to sivelestat. Methods and Results An in vitro HNE inhibition assay was employed to screen a series of triterpenes. Six pentacyclic triterpenes, but not tetracyclic triterpenes, significantly inhibited HNE. Of these pentacyclic triterpenes, ursolic acid exhibited the highest inhibitory potency (IC50 = 5.51 µM). The HNE inhibitory activity of ursolic acid was further verified using a mouse model of acute smoke-induced lung inflammation. The results of nuclear magnetic resonance and HNE inhibition kinetic analysis showed that the pentacyclic triterpenes competitively and reversibly inhibited HNE. Molecular docking experiments indicated that the molecular scaffold, 28-COOH, and a double bond at an appropriate location in the pentacyclic triterpenes are important for their inhibitory activity. Conclusion Our results provide insights into the effects of pentacyclic triterpenes on lung inflammatory actions through reversible inhibition of HNE activity.

Bis-triazolyl indoleamines as unique “off–approach–on” chemosensors for copper and fluorine

Abstract: Bis-triazolyl indoleamine-based chemosensors that respond to copper, and then fluorine as presumably facilitated by the high-affinity interaction between F− and the NH-proton of indole, are reported. Remarkable fluorimetric as well as colorimetric alternations upon the specific ligand–ion recognitions were observed.

Benzbromarone, an old uricosuric drug, inhibits human fatty acid binding protein 4 in vitro and lowers the blood glucose level in db/db mice

Abstract: Fatty acid-binding protein 4 (FABP4) plays an important role in maintaining glucose and lipid homeostasis. The aim of this study was to find new inhibitors of FABP4 for the treatment of type 2 diabetes. Human FABP4 protein was expressed, and its inhibitors were detected in 1,8-ANS displacement assay. The effect of the inhibitor on lipolysis activity was examined in mouse 3T3-L1 preadipocytes. The db/db mice were used to evaluate the anti-diabetic activity of the inhibitor. Molecular docking and site-directed mutagenesis studies were carried out to explore the binding mode between the inhibitor and FABP4. From 232 compounds tested, benzbromarone (BBR), an old uricosuric drug, was discovered to be the best inhibitor of FABP4 with an IC50 value of 14.8 μmol/L. Furthermore, BBR (25 μmol/L) significantly inhibited forskolin-stimulated lipolysis in 3T3-L1 cells. Oral administration of BBR (25 or 50 mg/kg, for 4 weeks) dose-dependently reduced the blood glucose level and improved glucose tolerance and insulin resistance in db/db mice. Molecular docking revealed that the residues Ser55, Asp76, and Arg126 of FABP4 formed important interactions with BBR, which was confirmed by site-directed mutagenesis studies. BBR is an inhibitor of FABP4 and a potential drug candidate for the treatment of type 2 diabetes and atherosclerosis.

Combinatorial pharmacophore modeling of organic cation transporter 2 (OCT2) inhibitors: insights into multiple inhibitory mechanisms.

Abstract: Organic cation transporter 2 (OCT2) is responsible for the entry step of many drugs in renal elimination, of which the changing activity may cause unwanted drug-drug interactions (DDIs). To develop drugs with favorable safety profile and provide instruction for rational clinical drug administration, it is of great interest to investigate the multiple mechanisms of OCT2 inhibition. In this study, we designed a combinatorial scheme to screen the optimum combination of pharmacophores from a pool of hypotheses established based on 162 OCT2 inhibitors. Among them, one single pharmacophore hypothesis represents a potential binding mode that may account for one unique inhibitory mechanism, and the obtained pharmacophore combination describes the multimechanisms of OCT2 inhibition. The final model consists of four individual pharmacophores, i.e., DHPR18, APR2, PRR5 and HHR4. Given a query ligand, it is considered as an inhibitor if it matches at least one of the hypotheses, or a noninhibitor if it fails to match any of four hypotheses. Our combinatorial pharmacophore model performs reasonably well to discriminate inhibitors and noninhibitors, yielding an overall accuracy around 0.70 for a test set containing 81 OCT2 inhibitors and 218 noninhibitors. Intriguingly, we found that the number of matched hypotheses was positively correlated with inhibition rate, which coincides with the pharmacophore modeling result of P-gp substrate binding. Further analysis suggested that the hypothesis PRR5 was responsible for competitive inhibition of OCT2, and other hypotheses were important for interaction between the inhibitor and OCT2. In light of the results, a hypothetical model for inhibiting transporting mediated by OCT2 was proposed.

Review of melt casting of dense ceramics and glasses by high gravity combustion synthesis

Abstract: High gravity combustion synthesis is a recently reported technique to prepare dense ceramics and glasses by melt casting instead of conventional powder sintering. This technique combines strong exothermic chemical reactions with a high gravity field, and offers an efficient and furnace free way for rapid production of bulk ceramic and glass materials. This article reviews major results on melt casting of dense ceramics and glasses by high gravity combustion synthesis. Several ceramic and glass materials prepared by high gravity combustion synthesis are firstly presented as examples, including single phase ceramics, multiphase eutectic or composite ceramics, glasses and glass–ceramics. Then, the reaction kinetics in high gravity combustion synthesis are discussed in detail, with an emphasis on phase separation, solidification and microstructure evolution. Finally, a conclusion is drawn with a perspective on further development and application of high gravity combustion synthesis.

Revisit of a dipropargyl rhodamine probe reveals its alternative ion sensitivity in both a solution and live cells

Abstract: This study reveals that a dipropargyl rhodamine B derivative previously described as a reaction-based irreversible palladium probe responds, however, more sensitively to mercury with a reversible “turn-on” fluorescence. The probe also shows a much better imaging ability for mercury than for palladium in live cells.

Identification of Novel Small Molecules as Inhibitors of Hepatitis C Virus by Structure-Based Virtual Screening

Abstract: Hepatitis C virus (HCV) NS3/NS4A serine protease is essential for viral replication, which is regarded as a promising drug target for developing direct-acting anti-HCV agents. In this study, sixteen novel compounds with cell-based HCV replicon activity ranging from 3.0 to 28.2 μM (IC50) were successfully identified by means of structure-based virtual screening. Compound 5 and compound 11, with an IC50 of 3.0 μM and 5.1 μM, respectively, are the two most potent molecules with low cytotoxicity.

Thiophene [3, 2-d] combined pyrimidine-4-ketone compound and preparation method thereof and medicine combination and application

Abstract: The invention relates to a thiophene [3, 2-d] combined pyrimidine-4-ketone compound and a preparation method thereof and a medicine combination and pharmacological application. A structure general formula is showed in a formula (I). The compound has good inhibiting effect to DDPIV (dipeptide kininase IV) and is a strong DDPIV inhibitor and capable of indirectly improving content of glucagon-like peptide-1 (GLP-1) in a body so that a series of physiological effects are caused in the body, the purpose of type 2 diabetes treatment is achieved and the compound is hopeful of being developed to a new diabetes treatment medicine.

Diaryl[a, g]quinolizidine compound, preparation method therefor, pharmaceutical composition, and uses thereof

Abstract: The present invention relates to a diarylo[a,g]quinolizidine compound of formula (I), enantiomer, diastereoisomer, racemate, mixture, pharmaceutically acceptable salt, crystalline hydrate or solvate thereof; the preparation method thereof, and uses thereof in preparing an experimental model drugs related to dopamine receptors and 5-HT receptors or a medicament for treating or preventing a disease related to dopamine receptors and 5-HT receptors.

Fluorine substituted cyclic amine compounds and preparation methods, pharmaceutical compositions, and uses thereof

Abstract: The present invention relates to the field of pharmaceutical chemistry and pharmacotherapeutics, and in particular to compounds of general formula I, racemates, R-isomers, S-isomers, and pharmaceutically acceptable salts thereof and their mixtures, and the preparation methods thereof and a pharmaceutical composition containing the compounds and uses thereof as an acetylcholine esterase inhibitor.

Review of Melt Casting of Dense Ceramics and Glasses by High Gravity Combustion Synthesis

Abstract: High gravity combustion synthesis is a recently reported technique to prepare dense ceramics and glasses by melt casting instead of conventional powder sintering. This technique combines strong exothermic chemical reactions with a high gravity field, and offers an efficient and furnace free way for rapid production of bulk ceramic and glass materials. This article reviews major results on melt casting of dense ceramics and glasses by high gravity combustion synthesis. Several ceramic and glass materials prepared by high gravity combustion synthesis are firstly presented as examples, including single phase ceramics, multiphase eutectic or composite ceramics, glasses and glass–ceramics. Then, the reaction kinetics in high gravity combustion synthesis are discussed in detail, with an emphasis on phase separation, solidification and microstructure evolution. Finally, a conclusion is drawn with a perspective on further development and application of high gravity combustion synthesis.