Publications (157) View all
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Article: Enhanced photocatalytic properties of titania-graphene nanocomposites: a density functional theory study.
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ABSTRACT: In this work, we systematically studied the mechanism for the enhanced photocatalytic activities of TiO2-graphene composites by using density functional theory (DFT) calculations. The studied composites include: TiO2-pristine graphene, TiO2-graphene with defect, as well as TiO2-graphene oxide. The results from geometry optimization can reveal information about the interface structure and anchoring orientation of the composites. The calculated electronic properties including total and difference charge density, as well as charge population, demonstrate the polarization and electron redistribution for the composites. Projected density of states and energy bands can provide some useful information about the photocatalytic mechanism involving the electrons excitation from the O-2p orbital on the valence band to the C-2p on the conduction band maximum for the composites. The results of our study can provide some useful information for understanding the detailed molecular mechanism of the better performance of composites compared to the individual components.Physical Chemistry Chemical Physics 03/2013; · 3.57 Impact Factor -
Article: Exploring the Molecular Mechanism of Cross-Resistance to HIV-1 Integrase Strand Transfer Inhibitors by Molecular Dynamics Simulation and Residue Interaction Network Analysis.
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ABSTRACT: The rapid emergence of cross-resistance to the integrase strand transfer inhibitors (INSTIs) has become a serious problem in the therapy of human immunodeficiency virus type 1 (HIV-1) infection. Understanding the detailed molecular mechanism of INSTIs cross-resistance is therefore critical for the development of new effective therapy against cross-resistance. On the basis of the homology modeling constructed structure of tetrameric HIV-1 intasome, the detailed molecular mechanism of the cross-resistance mutation E138K/Q148K to three important INSTIs (Raltegravir (RAL, FDA approved in 2007), Elvitegravir (EVG, FDA approved in 2012), Dolutegravir (DTG, Phase III clinical trials)) was investigated by using molecular dynamics (MD) simulation and residue interaction network (RIN) analysis. The results from conformation analysis and binding free energy calculation can provide some useful information about the detailed binding mode and cross-resistance mechanism for the three INSTIs to HIV-1 intasome. Binding free energy decomposition analysis revealed that Pro145 residue in the 140s 1oop (Gly140 to Gly149) of the HIV-1 intasome had strong hydrophobic interactions with INSTIs and played an important role in the binding of INSTIs to HIV-1 intasome active site. A systematic comparison and analysis of the RIN proves that the communications between the residues in the resistance mutant is increased when compared with that of the wild-type HIV-1 intasome. Further analysis indicates that residue Pro145 may play an important role and is relevant to the structure rearrangement in HIV-1 intasome active site. In addition, the chelating ability of the oxygen atoms in INSTIs (e.g., RAL and EVG) to Mg2+ in the active site of the mutated intasome was reduced due to this conformational change and is also responsible for the cross-resistance mechanism. Notably, the cross-resistance mechanism we proposed could give some important information for the future rational design of novel INSTIs overcoming cross-resistance. Furthermore, the combination use of molecular dynamics simulation and residue interaction network analysis can be generally applicable to investigate drug resistance mechanism for other biomolecular systems.Journal of Chemical Information and Modeling 12/2012; · 4.68 Impact Factor -
Article: Molecular dynamics and free energy studies on Aurora kinase A and its mutant bound with MLN8054: insight into molecular mechanism of subtype selectivity.
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ABSTRACT: Because of the high conservation of ATP-binding sites in kinases, the quest for selective kinase inhibitors has been increasingly urgent in recent years. The Aurora kinase family represents attractive targets in cancer therapy and several small molecule inhibitors targeting Aurora kinases are undergoing clinical trials. Among them, MLN8054 has been proved to be a selective Aurora-A inhibitor, and is currently being evaluated in a phase I trial for patients with advanced solid tumors. But the detailed selectivity mechanism of MLN8054 towards Aurora-A over Aurora-B is still not resolved. In the present work, this selectivity mechanism was investigated using molecular dynamics simulations and binding free energy calculations. The predicted binding conformations and binding affinities of MLN8054 to Aurora-A and its mutant that mimics Aurora-B suggest that there exists stronger interaction between MLN8054 and Aurora-A through an induced DFG-up conformation. Further analyses can provide some information about the structural basis for the selectivity mechanism. Binding of MLN8054 to Aurora-A induces the conformation of the activation loop to adopt an unusual DFG-up conformation and opens the hydrophobic pocket of the active site, thus increasing the interaction between MLN8054 and the residue Val279. The residue Glu177 in Aurora-B displays electrostatic repulsion with MLN8054, while the corresponding Thr217 in Aurora-A has favorable interactions with MLN8054. The conformation change and the difference between the binding pockets for Aurora-A and B are key factors responsible for the selectivity. The results could be helpful for the rational design of selective inhibitors of Aurora-A kinase.Molecular BioSystems 09/2012; 8(11):3049-60. · 3.53 Impact Factor -
Article: Understanding the structural and energetic basis of inhibitor and substrate bound to the full-length NS3/4A: insights from molecular dynamics simulation, binding free energy calculation and network analysis.
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ABSTRACT: Hepatitis C virus (HCV) bifunctional NS3/4A is an attractive anti-HCV drug target, as both the protease and helicase functions are required for viral infection and replication. Although the first generation of NS3/4A protease inhibitors (PIs) has focused almost exclusively on the interaction with the protease domain alone, recent studies have shown that PIs also inhibit the full-length NS3/4A protein. However, the detailed molecular mechanism of the interaction between protease inhibitors, as well as the peptide substance with the full-length NS3/4A protein, remains poorly understood. Herein, starting from the recently determined crystal structure of an inhibitor (inhibitor ) bound to the full-length NS3/4A protein, the structures of the full-length NS3/4A complexed with inhibitor ITMN-191 (by InterMune/Roche; Phase II) and substrate 4B5A (the viral cleavage product peptide) were built. Then, residue interaction network (RIN) analysis, molecular dynamics (MD) simulation, binding free energy calculation, decomposition of free energies on per-residue and dynamic substrate recognition pattern analysis were employed to uncover the structural and energetic basis of inhibitor and substrate binding mode in the binding cleft located at the interface of the protease and helicase domains of the full-length NS3/4A. The results from our study reveal that both the protease and helicase residues of the NS3/4A participate in the interactions with the inhibitor , ITMN-191 and 4B5A. Additional analysis of the NS3/4A substrate and inhibitor envelopes reveals the areas where the consensus inhibitor volume extended beyond the substrate envelope. These areas correspond to drug resistance mutations including Arg155, Ala156 and Asp168 at the protease active site as well as the two conserved helicase residues Gln526 and His528 that strongly interact with the inhibitors. Thus, the findings of this study will be very useful for understanding the interaction mechanism between the inhibitor (substrate) and NS3/4A and also for the rational design and development of new potent molecules targeting the full-length NS3/4A.Molecular BioSystems 07/2012; 8(10):2753-65. · 3.53 Impact Factor -
Article: Quantitative structure-activity relationship analysis of a series of human renal organic anion transporter inhibitors.
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ABSTRACT: Organic anion transporters (OATs) have been proved to play important roles in the membrane transport of numerous potentially toxic xenobiotics, drugs, and endogenous metabolites. In general, OATs substrates can compete with one another for the transporter to mutually decrease renal secretion and thus delay the clearance and prolong the duration of action of each compound. Such interactions have the potential to bring about adverse outcomes for clinical cases. Therefore, it is very important to assess the molecular bioactivity to inhibit OATs during the development of new drugs and co-administration. In this work, the relationships between 45 chemicals and their corresponding hOAT1 and hOAT3 inhibitory activities were analyzed. The quantitative structure-activity relationship (QSAR) model was developed by genetic algorithm and multiple linear regression method. The predictive power of the proposed model was strictly evaluated, and the applicability domain was also defined. The proposed models were robust and satisfactory and could provide a feasible and effective tool for hOAT1 or hOAT3 inhibitor screening.Archiv der Pharmazie 07/2012; 345(10):759-66. · 1.71 Impact Factor
