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61.
Chandrasekaran Meganathan Sugunadevi Sakkiah Yuno Lee Jayavelu Venkat Narayanan Keun Woo Lee 《Journal of molecular modeling》2013,19(2):715-726
In our study, a structure-based virtual screening study was conducted to identify potent ITK inhibitors, as ITK is considered to play an important role in the treatment of inflammatory diseases. We developed a structure-based pharmacophore model using the crystal structure (PDB ID: 3MJ2) of ITK complexed with BMS-50944. The most predictive model, SB-Hypo1, consisted of six features: three hydrogen-bond acceptors (HBA), one hydrogen-bond donor (HBD), one ring aromatic (RA), and one hydrophobic (HY). The statistical significance of SB-Hypo1 was validated using wide range of test set molecules and a decoy set. The resulting well-validated model could then be confidently used as a 3D query to screen for drug-like molecules in a database, in order to retrieve new chemical scaffolds that may be potent ITK inhibitors. The hits retrieved from this search were filtered based on the maximum fit value, drug-likeness, and ADMET properties, and the hits that were retained were used in a molecular docking study to find the binding mode and molecular interactions with crucial residues at the active site of the protein. These hits were then fed into a molecular dynamics simulation to study the flexibility of the activation loop of ITK upon ligand binding. This combination of methodologies is a valuable tool for identifying structurally diverse molecules with desired biological activities, and for designing new classes of selective ITK inhibitors. Figure
A structure-based pharmacophore model was developed, using a fully resolved crystal structure, in order to identify novel virtual lead compounds for use in ITK inhibitor design 相似文献
62.
We isolated a Staphylococcus aureus strain HPC-250 producing antibacterial agent against Paenibacillus strain HPC-251. Both strains were isolated from the same environmental niche. The bacteria were identified using the partial
sequencing of their TA-cloned 16S rDNA. Spectrum of the antibacterial agent was also tested against routine observed bacteria
with drinking water contamination such as Escherichia coli, Salmonella, Pseudomonas, and Vibrio and these were found to be sensitive. Bacteria like Acinetobacter and Burkholderia were found to be resistant. The differential antibacterial activity of the HPC-250 was observed for the genus Bacillus where
B. subtilis remained resistant although B. sphaericus was sensitive. 相似文献
63.
Human immunodeficiency virus type 1 Vpr interacts with antiapoptotic mitochondrial protein HAX-1 下载免费PDF全文
Yedavalli VS Shih HM Chiang YP Lu CY Chang LY Chen MY Chuang CY Dayton AI Jeang KT Huang LM 《Journal of virology》2005,79(21):13735-13746
Human immunodeficiency virus type 1 viral protein R (Vpr) is required for viral pathogenesis and has been implicated in T-cell apoptosis through its activation of caspase 3 and caspase 9 and perturbation of mitochondrial membrane potential. To understand better Vpr-mitochondria interaction, we report here the identification of antiapoptotic mitochondrial protein HAX-1 as a novel Vpr target. We show that Vpr and HAX-1 physically associate with each other. Overexpression of Vpr in cells dislocates HAX-1 from its normal residence in mitochondria and creates mitochondrion instability and cell death. Conversely, overexpression of HAX-1 suppressed the proapoptotic activity of Vpr. 相似文献
64.
Reddy MV Mallireddigari MR Pallela VR Venkatapuram P Boominathan R Bell SC Reddy EP 《Bioorganic & medicinal chemistry》2005,13(5):1715-1723
A new series of styryl acetoxyphenyl sulfides and sulfones possessing (E)- and (Z)-configurations were designed and prepared by stereospecific syntheses. All these compounds were evaluated for their ability to inhibit COX-2 enzyme in vitro. Structure-activity relationship studies on these compounds revealed that only sulfides with (Z)-configuration have potential COX-2 inhibitory activity. This inactivation of the enzyme is believed to be due to the selective covalent modification of COX-2 by the inhibitors. 相似文献
65.
De novo designed beta-hairpin peptides have generally been recalcitrant to crystallization. The crystal structures of four synthetic peptide beta-hairpins, Boc-Leu-Val-Val-DPro-Gly-Leu-Phe-Val-OMe (1), Boc-Leu-Phe-Val-DPro-Ala-Leu-Phe-Val-OMe (2), Boc-Leu-Val-Val-DPro-Aib-Leu-Val-Val-OMe (3), and Boc-Met-Leu-Phe-Val-DPro-Ala-Leu-Val-Val-Phe-OMe (4), are described. The centrally positioned DPro-Xxx segment promotes prime beta-turn formation, thereby nucleating beta-hairpin structures. In all four peptides well-defined beta-hairpins nucleated by central type II' DPro-Xxx beta-turns have been characterized by X-ray diffraction, providing a view of eight crystallographically independent hairpins. In peptides 1-3 three intramolecular cross-strand hydrogen bonds stabilized the observed beta-hairpin, with some fraying of the structures at the termini. In peptide 4, four intramolecular cross-strand hydrogen bonds stabilized the hairpin. Peptides 1-4 reveal common features of packing of beta-hairpins into crystals. Two-dimensional sheet formation mediated by intermolecular hydrogen bonds formed between antiparallel strands of adjacent molecule is a recurrent theme. The packing of two-dimensional sheets into the crystals is mediated in the third dimension by bridging solvents and interactions of projecting side chains, which are oriented on either face of the sheet. In all cases, solvation of the central DPro-Xxx peptide unit beta-turn is observed. The hairpins formed in the octapeptides are significantly buckled as compared to the larger hairpin in peptide 4, which is much flatter. The crystal structures provide insights into the possible modes of beta-sheet packing in regular crystalline arrays, which may provide a starting point for understanding beta-sandwich and cross-beta-structures in amyloid fibrils. 相似文献
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The formation of local structure, in short peptides has been probed by examining cleavage patterns and rates of proteolysis of designed sequences with a high tendency to form beta-hairpin structures. Three model sequences which bear fluorescence donor and acceptor groups have been investigated: [see text]. Fluorescence resonance energy transfer (FRET) provides a convenient probe for peptide cleavage. MALDI mass spectrometry has been used to probe sites of cleavage and CD spectroscopy to access the overall backbone conformation using analog sequences, which lack strongly absorbing donor and acceptor groups. The proteases trypsin, subtilisin, collagenase, elastase, proteinase K and thermolysin were used for proteolysis and the rates of cleavage determined. Peptide 3 is the most susceptible to cleavage by all the enzymes except thermolysin, which cleaves all three peptides at comparable rates. Peptides 1 and 2 are completely resistant to the action of trypsin, suggesting that beta-turn formation acts as a deterrent to proteolytic cleavage. 相似文献
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