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Juliana S Luz Celso RR Ramos Márcia CT Santos Patricia P Coltri Fernando L Palhano Debora Foguel Nilson IT Zanchin Carla C Oliveira 《BMC biochemistry》2010,11(1):22
Background
The archaeal exosome is formed by a hexameric RNase PH ring and three RNA binding subunits and has been shown to bind and degrade RNA in vitro. Despite extensive studies on the eukaryotic exosome and on the proteins interacting with this complex, little information is yet available on the identification and function of archaeal exosome regulatory factors. 相似文献3.
Discovery of a Highly Selective Glycogen Synthase Kinase‐3 Inhibitor (PF‐04802367) That Modulates Tau Phosphorylation in the Brain: Translation for PET Neuroimaging 下载免费PDF全文
Prof. Dr. Steven H. Liang Dr. Jinshan Michael Chen Prof. Dr. Marc D. Normandin Dr. Jeanne S. Chang Dr. George C. Chang Dr. Christine K. Taylor Dr. Patrick Trapa Dr. Mark S. Plummer Dr. Kimberly S. Para Dr. Edward L. Conn Dr. Lori Lopresti‐Morrow Dr. Lorraine F. Lanyon Dr. James M. Cook Dr. Karl E. G. Richter Dr. Charlie E. Nolan Dr. Joel B. Schachter Dr. Fouad Janat Dr. Ye Che Dr. Veerabahu Shanmugasundaram Dr. Bruce A. Lefker Dr. Bradley E. Enerson Prof. Dr. Elijahu Livni Lu Wang Dr. Nicolas J. Guehl Dr. Debasis Patnaik Florence F. Wagner Prof. Dr. Roy Perlis Dr. Edward B. Holson Prof. Dr. Stephen J. Haggarty Prof. Dr. Georges El Fakhri Dr. Ravi G. Kurumbail Prof. Dr. Neil Vasdev 《Angewandte Chemie (International ed. in English)》2016,55(33):9601-9605
Glycogen synthase kinase‐3 (GSK‐3) regulates multiple cellular processes in diabetes, oncology, and neurology. N‐(3‐(1H‐1,2,4‐triazol‐1‐yl)propyl)‐5‐(3‐chloro‐4‐methoxyphenyl)oxazole‐4‐carboxamide (PF‐04802367 or PF‐367) has been identified as a highly potent inhibitor, which is among the most selective antagonists of GSK‐3 to date. Its efficacy was demonstrated in modulation of tau phosphorylation in vitro and in vivo. Whereas the kinetics of PF‐367 binding in brain tissues are too fast for an effective therapeutic agent, the pharmacokinetic profile of PF‐367 is ideal for discovery of radiopharmaceuticals for GSK‐3 in the central nervous system. A 11C‐isotopologue of PF‐367 was synthesized and preliminary PET imaging studies in non‐human primates confirmed that we have overcome the two major obstacles for imaging GSK‐3, namely, reasonable brain permeability and displaceable binding. 相似文献
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Xing L Kurumbail RG Frazier RB Davies MS Fujiwara H Weinberg RA Gierse JK Caspers N Carter JS McDonald JJ Moore WM Vazquez ML 《Journal of computer-aided molecular design》2009,23(1):13-24
Inducible, microsomal prostaglandin E synthase 1 (mPGES-1), the terminal enzyme in the prostaglandin (PG) biosynthetic pathway,
constitutes a promising therapeutic target for the development of new anti-inflammatory drugs. To elucidate structure–function
relationships and to enable structure-based design, an mPGES-1 homology model was developed using the three-dimensional structure
of the closest homologue of the MAPEG family (Membrane Associated Proteins in Eicosanoid and Glutathione metabolism), mGST-1.
The ensuing model of mPGES-1 is a homo-trimer, with each monomer consisting of four membrane-spanning segments. Extensive
structure refinement revealed an inter-monomer salt bridge (K26-E77) as well as inter-helical interactions within each monomer,
including polar hydrogen bonds (e.g. T78-R110-T129) and hydrophobic π-stacking (F82-F103-F106), all contributing to the overall
stability of the homo-trimer of mPGES-1. Catalytic co-factor glutathione (GSH) was docked into the mPGES-1 model by flexible
optimization of both the ligand and the protein conformations, starting from the initial location ascertained from the mGST-1
structure. Possible binding site for the substrate, prostaglandin H2 (PGH2), was identified by systematically probing the refined molecular structure of mPGES-1. A binding model was generated by induced
fit docking of PGH2 in the presence of GSH. The homology model prescribes three potential inhibitor binding sites per mPGES-1 trimer. This was
further confirmed experimentally by equilibrium dialysis study which generated a binding stoichiometric ratio of approximately
three inhibitor molecules to three mPGES-1 monomers. The structural model that we have derived could serve as a useful tool
for structure-guided design of inhibitors for this emergently important therapeutic target. 相似文献
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Renata Monteiro-Maia Maria B Ortigão-de-Sampaio Rosa T Pinho Luiz RR Castello-Branco 《Journal of immune based therapies and vaccines》2006,4(1):1-6
We hypothesize that the energy strategy of a cell is a key factor for determining how, or if, the immune system interacts
with that cell. Cells have a limited number of metabolic states, in part, depending on the type of fuels the cell consumes.
Cellular fuels include glucose (carbohydrates), lipids (fats), and proteins. We propose that the cell's ability to switch
to, and efficiently use, fat for fuel confers immune privilege. Additionally, because uncoupling proteins are involved in
the fat burning process and reportedly in protection from free radicals, we hypothesize that uncoupling proteins play an important
role in immune privilege. Thus, changes in metabolism (caused by oxidative stresses, fuel availability, age, hormones, radiation,
or drugs) will dictate and initiate changes in immune recognition and in the nature of the immune response. This has profound
implications for controlling the symptoms of autoimmune diseases, for preventing graft rejection, and for targeting tumor
cells for destruction. 相似文献
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Ashrafullah Khan Shafi Ullah Khan Adnan Khan Bushra Shal Sabih Ur Rehman Shaheed Ur Rehman Thet Thet Htar Salman Khan Sirajudheen Anwar Ahmed Alafnan Kannan RR Rengasamy 《Molecules (Basel, Switzerland)》2022,27(13)
Plants are an important source of drug development and numerous plant derived molecules have been used in clinical practice for the ailment of various diseases. The Toll-like receptor-4 (TLR-4) signaling pathway plays a crucial role in inflammation including rheumatoid arthritis. The TLR-4 binds with pro-inflammatory ligands such as lipopolysaccharide (LPS) to induce the downstream signaling mechanism such as nuclear factor κappa B (NF-κB) and mitogen activated protein kinases (MAPKs). This signaling activation leads to the onset of various diseases including inflammation. In the present study, 22 natural compounds were studied against TLR-4/AP-1 signaling, which is implicated in the inflammatory process using a computational approach. These compounds belong to various classes such as methylxanthine, sesquiterpene lactone, alkaloid, flavone glycosides, lignan, phenolic acid, etc. The compounds exhibited different binding affinities with the TLR-4, JNK, NF-κB, and AP-1 protein due to the formation of multiple hydrophilic and hydrophobic interactions. With TLR-4, rutin had the highest binding energy (−10.4 kcal/mol), poncirin had the highest binding energy (−9.4 kcal/mol) with NF-κB and JNK (−9.5 kcal/mol), respectively, and icariin had the highest binding affinity (−9.1 kcal/mol) with the AP-1 protein. The root means square deviation (RMSD), root mean square fraction (RMSF), and radius of gyration (RoG) for 150 ns were calculated using molecular dynamic simulation (MD simulation) based on rutin’s greatest binding energy with TLR-4. The RMSD, RMSF, and RoG were all within acceptable limits in the MD simulation, and the complex remained stable for 150 ns. Furthermore, these compounds were assessed for the potential toxic effect on various organs such as the liver, heart, genotoxicity, and oral maximum toxic dose. Moreover, the blood–brain barrier permeability and intestinal absorption were also predicted using SwissADME software (Lausanne, Switzerland). These compounds exhibited promising physico-chemical as well as drug-likeness properties. Consequently, these selected compounds portray promising anti-inflammatory and drug-likeness properties. 相似文献
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VG Adlakha RR Vemuganti 《International Journal of Mathematical Education in Science & Technology》2013,44(5):708-713
In many practical situations scaling the data is necessary to solve linear programs. This note explores the relationships in translating the sensitivity analysis between the original and the scaled problems. 相似文献
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Renata Monteiro-Maia Maria B Ortig?o-de-Sampaio Rosa T Pinho Luiz RR Castello-Branco 《Journal of immune based therapies and vaccines》2006,4(1):4