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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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Ravindra P. Jumde Melissa Guardigni Robin M. Gierse Alaa Alhayek Di Zhu Zhoor Hamid Sandra Johannsen Walid A. M. Elgaher Philipp J. Neusens Christian Nehls Jrg Haupenthal Norbert Reiling Anna K. H. Hirsch 《Chemical science》2021,12(22):7775
Target-directed dynamic combinatorial chemistry (tdDCC) enables identification, as well as optimization of ligands for un(der)explored targets such as the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase (DXPS). We report the use of tdDCC to first identify and subsequently optimize binders/inhibitors of the anti-infective target DXPS. The initial hits were also optimized for their antibacterial activity against E. coli and M. tuberculosis during subsequent tdDCC runs. Using tdDCC, we were able to generate acylhydrazone-based inhibitors of DXPS. The tailored tdDCC runs also provided insights into the structure–activity relationship of this novel class of DXPS inhibitors. The competition tdDCC runs provided important information about the mode of inhibition of acylhydrazone-based inhibitors. This approach holds the potential to expedite the drug-discovery process and should be applicable to a range of biological targets.Target-directed dynamic combinatorial chemistry was used for hit-identification and subsequent hit-optimization for the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase resulting in novel inhibitors with low micromolar affinities. 相似文献
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MK Hossain-Ibrahim K Rezajooi JK MacNally MRJ Mason AR Lieberman PN Anderson 《BMC neuroscience》2006,7(1):8-21
Background
Inflammation around cell bodies of primary sensory neurons and retinal ganglion cells enhances expression of neuronal growth-associated genes and stimulates axonal regeneration. We have asked if inflammation would have similar effects on corticospinal neurons, which normally show little response to spinal cord injury. Lipopolysaccharide (LPS) was applied onto the pial surface of the motor cortex of adult rats with or without concomitant injury of the corticospinal tract at C4. Inflammation around corticospinal tract cell bodies in the motor cortex was assessed by immunohistochemistry for OX42 (a microglia and macrophage marker). Expression of growth-associated genes c-jun, ATF3, SCG10 and GAP-43 was investigated by immunohistochemistry or in situ hybridisation. 相似文献4.
The nucleide 73Kr has been identified by on-line mass separation as a precursor of β-delayed proton emission. The proton branch is (6.8 ±1.2) × 10−3 proton/decay. The protons populate the ground state and also the first excited 2+ state at 866 keV in 72Se with a relative intensity of (35±9) %. The value of QEC−Bp, where Bp is the proton separation energy for the nucleus 73Br, is found to be 4.85 ±0.30 MeV based on the fraction of proton events preceded by positron decay. 相似文献
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