Showing papers by "Kaixian Chen published in 2009"

A Simple and Convenient Copper-Catalyzed Tandem Synthesis of Quinoline-2-carboxylates at Room Temperature

Abstract: We developed a simple and convenient copper-catalyzed method for the synthesis of quinoline-2-carboxylate derivatives through sequential intermolecular addition of alkynes onto imines and subsequent intramolecular ring closure by arylation. The efficiency of this system allowed the reactions to be carried out at room temperature.

Mechanism of NS2B-Mediated Activation of NS3pro in Dengue Virus: Molecular Dynamics Simulations and Bioassays

Abstract: The NS2B cofactor is critical for proteolytic activation of the flavivirus NS3 protease. To elucidate the mechanism involved in NS2B-mediated activation of NS3 protease, molecular dynamic simulation, principal component analysis, molecular docking, mutagenesis, and bioassay studies were carried out on both the dengue virus NS3pro and NS2B-NS3pro systems. The results revealed that the NS2B-NS3pro complex is more rigid than NS3pro alone due to its robust hydrogen bond and hydrophobic interaction networks within the complex. These potent networks lead to remodeling of the secondary and tertiary structures of the protease that facilitates cleavage sequence recognition and binding of substrates. The cofactor is also essential for proper domain motion that contributes to substrate binding. Hence, the NS2B cofactor plays a dual role in enzyme activation by facilitating the refolding of the NS3pro domain as well as being directly involved in substrate binding/interactions. Kinetic analyses indicated for the first time that Glu92 and Asp50 in NS2B and Gln27, Gln35, and Arg54 in NS3pro may provide secondary interaction points for substrate binding. These new insights on the mechanistic contributions of the NS2B cofactor to NS3 activation may be utilized to refine current computer-based search strategies to raise the quality of candidate molecules identified as potent inhibitors against flaviviruses.

Lys169 of human glucokinase is a determinant for glucose phosphorylation: implication for the atomic mechanism of glucokinase catalysis.

Abstract: Glucokinase (GK), a glucose sensor, maintains plasma glucose homeostasis via phosphorylation of glucose and is a potential therapeutic target for treating maturity-onset diabetes of the young (MODY) and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). To characterize the catalytic mechanism of glucose phosphorylation by GK, we combined molecular modeling, molecular dynamics (MD) simulations, quantum mechanics/molecular mechanics (QM/MM) calculations, experimental mutagenesis and enzymatic kinetic analysis on both wild-type and mutated GK. Our three-dimensional (3D) model of the GK-Mg(2+)-ATP-glucose (GMAG) complex, is in agreement with a large number of mutagenesis data, and elucidates atomic information of the catalytic site in GK for glucose phosphorylation. A 10-ns MD simulation of the GMAG complex revealed that Lys169 plays a dominant role in glucose phosphorylation. This prediction was verified by experimental mutagenesis of GK (K169A) and enzymatic kinetic analyses of glucose phosphorylation. QM/MM calculations were further used to study the role of Lys169 in the catalytic mechanism of the glucose phosphorylation and we found that Lys169 enhances the binding of GK with both ATP and glucose by serving as a bridge between ATP and glucose. More importantly, Lys169 directly participates in the glucose phosphorylation as a general acid catalyst. Our findings provide mechanistic details of glucose phorphorylation catalyzed by GK, and are important for understanding the pathogenic mechanism of MODY.

Current strategies for the discovery of K+ channel modulators.

Abstract: Potassium ion (K(+)) channels consist of a ubiquitous family of membrane proteins that play critical roles in a wide variety of physiological processes, such as the regulation of neuronal excitability, muscle contraction, cell proliferation, and insulin secretion. Due to their pivotal functions in biological systems, K(+) channels have long been attractive targets for the rational drug design on the basis of their structures and interaction mechanisms. Various small-molecular compounds and toxins have been discovered to act as K(+) channel modulators. In the present review, we will first briefly discuss current knowledge of the structures and functions of K(+) channels, and then review the recent strategies for the discovery of K(+) channel modulators, focusing especially on the virtual screening approaches and chemical synthesis technologies.

Interaction Models of a Series of Oxadiazole-Substituted α-Isopropoxy Phenylpropanoic Acids Against PPARα and PPARγ: Molecular Modeling and Comparative Molecular Similarity Indices Analysis Studies

Abstract: Molecular recognition of a series of oxadiazole-substituted alpha-isopropoxy phenylpropanoic acids by PPARalpha and PPARgamma was investigated by using molecular modeling and 3D-QSAR analyses The binding models of these compounds were determined by hydrophobic property analyses and molecular docking procedure FlexX It was found that the hydrophilic heads of these compounds form four specific conserved hydrogen bonds with the ligand binding pockets of PPARalpha and PPARgamma, which results in fixed head conformations On the contrary, their hydrophobic tails adopt different configurations to make contacts with hydrophobic region The oxadiazole-ring-related hydrogen bond interactions well elucidate the structural features governing the different binding behavior of these agonists against PPARalpha and PPARgamma Based on these active conformations, highly predictive comparative molecular similarity indices analysis (CoMSIA) models were derived, which not only is consistent with the experimental results but also could be mapped back to the receptor topology and the ligand-receptor interaction models The simulation results reveal the structure-activity relationship of these compounds at the molecular level and provide new insights for the design of novel potent PPARalpha and PPARgamma dual agonists

Efficient Iron/Copper Cocatalyzed Alkynylation of Aryl Iodides with Terminal Alkynes.

Abstract: formula chem. We developed a highly efficient and practical protocol for the coupling of terminal alkynes with aryl iodides that is catalyzed by inexpensive and environmentally benign Fe/Cu. A broad spectrum of substrates can participate in the process effectively to produce desired products in good yields. The versatility, generality, low cost, and environmental friendliness, in combination with exceptionally high reaction rates, render this method particularly attractive for industrial applications.