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161.
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Yajun Zheng Colin M. Tice Suresh B. Singh 《Bioorganic & medicinal chemistry letters》2017,27(13):2825-2837
In structure-based drug design, the basic goal is to design molecules that fit complementarily to a given binding pocket. Since such computationally modeled molecules may not adopt the intended bound conformation outside the binding pocket, one challenge is to ensure that the designed ligands adopt similar low energy conformations both inside and outside of the binding pocket. Computational chemistry methods and conformational preferences of small molecules from PDB and Cambridge Structural Database (CSD) can be used to predict the bound structures of the designed molecules. Herein, we review applications of conformational control in structure-based drug design using selected examples from the recent medicinal chemistry literature. The main purpose is to highlight some intriguing conformational features that can be applied to other drug discovery programs. 相似文献
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During 30-months of storage at 4°C, potato (Solanum tuberosum L.) tubers progressively lose the ability to produce superoxide in response to wounding, resist microbial infection, and
develop a suberized wound periderm. Using differentially aged tubers, we demonstrate that Strboh A is responsible for the wound-induced oxidative burst in potato and aging attenuates its expression. In vivo superoxide production
and NADPH oxidase (NOX) activity from 1-month-old tubers increased to a maximum 18–24 h after wounding and then decreased
to barely detectable levels by 72 h. Wounding also induced a 68% increase in microsomal protein within 18 h. These wound-induced
responses were lost over a 25- to 30-month storage period. Superoxide production and NOX activity were inhibited by diphenylene
iodonium chloride, a specific inhibitor of NOX, which in turn effectively inhibited wound-healing and increased susceptibility
to microbial infection and decay in 1-month-old tubers. Wound-induced superoxide production was also inhibited by EGTA-mediated
destabilization of membranes. The ability to restore superoxide production to EGTA-treated tissue with Ca+2 declined with advancing tuber age, likely a consequence of age-related changes in membrane architecture. Of the five homologues
of NOX (Strboh A-D and F), wounding induced the expression of Strboh A in 6-month-old tubers but this response was absent in tubers stored for 25–30 months. Strboh
A thus mediates the initial burst of superoxide in response to wounding of potato tubers; loss of its expression increases
the susceptibility to microbial infection and contributes to the age-induced loss of wound-healing ability. 相似文献
166.
Baumgarten AM Suresh J May G Phillips RL 《TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik》2007,114(7):1229-1238
Quantitative trait loci (QTL) contributing to the frequency and severity of Ustilago maydis infection in the leaf, ear, stalk, and tassel of maize plants were mapped using an A188 × CMV3 and W23 × CMV3 recombinant
inbred (RI) populations. QTLs mapped to genetic bins 2.04 and 9.04–9.05 of the maize genome contributed strongly (R
2 = 18–28%) to variation in the frequency and severity of U. maydis infection over the entire plant in both populations and within the majority of environments. QTLs mapped to bins 3.05, 3.08,
and 8.00 in the A188 × CMV3 population and bin 4.05 in both populations significantly contributed to the frequency or severity
of infection in only the tassel tissue. QTLs mapped to bin 1.07 in the A188 × CMV3 population and bin 7.00 in the W23 × CMV3
population contributed to U. maydis resistance in only the ear tissue. Interestingly, the CMV3 allele of the QTL mapped to bin 1.10 in the A188 × CMV3 population
significantly contributed to U. maydis susceptibility in the ear and stalk but significantly increased resistance in the tassel tissue. Digenic epistatic interactions
between the QTL mapped to bin 5.08 and four distinct QTLs significantly contributed to the frequency and severity of infection
over the entire plant and within the tassel tissue of the A188 × CMV3 population. Several QTLs detected in this study mapped
to regions of the maize genome containing previously mapped U. maydis resistance QTLs and genes involved in plant disease resistance.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
167.
Shi LZ Faith NG Nakayama Y Suresh M Steinberg H Czuprynski CJ 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(10):6952-6962
The aryl hydrocarbon receptor (AhR) is part of a powerful signaling system that is triggered by xenobiotic agents such as polychlorinated hydrocarbons and polycyclic aromatic hydrocarbons. Although activation of the AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin or certain polycyclic aromatic hydrocarbons can lead to immunosuppression, there is also increasing evidence that the AhR regulates certain normal developmental processes. In this study, we asked whether the AhR plays a role in host resistance using murine listeriosis as an experimental system. Our data clearly demonstrate that AhR null C57BL/6J mice (AhR(-/-)) are more susceptible to listeriosis than AhR heterozygous (AhR(+/-)) littermates when inoculated i.v. with log-phase Listeria monocytogenes. AhR(-/-) mice exhibited greater numbers of CFU of L. monocytogenes in the spleen and liver, and greater histopathological changes in the liver than AhR(+/-) mice. Serum levels of IL-6, MCP-1, IFN-gamma, and TNF-alpha were comparable between L. monocytogenes-infected AhR(-/-) and AhR(+/-) mice. Increased levels of IL-12 and IL-10 were observed in L. monocytogenes-infected AhR(-/-) mice. No significant difference was found between AhR(+/-) and AhR(-/-) macrophages ex vivo with regard to their ability to ingest and inhibit intracellular growth of L. monocytogenes. Intracellular cytokine staining of CD4(+) and CD8(+) splenocytes for IFN-gamma and TNF-alpha revealed comparable T cell-mediated responses in AhR(-/-) and AhR(+/-) mice. Previously infected AhR(-/-) and AhR(+/-) mice both exhibited enhanced resistance to reinfection with L. monocytogenes. These data provide the first evidence that AhR is required for optimal resistance but is not essential for adaptive immune response to L. monocytogenes infection. 相似文献
168.
Complement contributes to inflammatory tissue destruction in a mouse model of Ross River virus-induced disease 总被引:1,自引:1,他引:0 下载免费PDF全文
Arthritogenic alphaviruses, including Ross River virus (RRV) and chikungunya virus, are mosquito-borne viruses that cause significant human disease worldwide, including explosive epidemics that can result in thousands to millions of infected individuals. Similar to infection of humans, infection of C57BL/6 mice with RRV results in severe monocytic inflammation of bone, joint, and skeletal muscle tissues. We demonstrate here that the complement system, an important component of the innate immune response, enhances the severity of RRV-induced disease in mice. Complement activation products were detected in the inflamed tissues and in the serum of RRV-infected wild-type mice. Furthermore, mice deficient in C3 (C3−/−), the central component of the complement system, developed much less severe disease signs than did wild-type mice. Complement-mediated chemotaxis is essential for many inflammatory arthritides; however, RRV-infected wild-type and C3−/− mice had similar numbers and composition of inflammatory infiltrates within hind limb skeletal muscle tissue. Despite similar inflammatory infiltrates, RRV-infected C3−/− mice exhibited far less severe destruction of skeletal muscle tissue. In addition to these studies, complement activation was also detected in synovial fluid from RRV-infected patients. Taken together, these findings indicate that complement activation occurs in the tissues of humans and mice infected with RRV and suggest that complement plays an essential role in the effector phase, but not the inductive phase, of RRV-induced arthritis and myositis. 相似文献
169.
Rajalingam D Kacer D Prudovsky I Kumar TK 《Biochemical and biophysical research communications》2007,360(3):604-608
Interleukin-1 alpha (IL-1alpha) regulates a wide range of important cellular processes. In this study for the first time, we report the cloning, expression, biophysical, and biological characterization of the human interleukin-1alpha. Human IL-1alpha has been expressed in Escherichia coli in high yields ( approximately 4mg per liter of the bacterial culture). The protein was purified to homogeneity ( approximately 98% purity) using affinity chromatography and size exclusion chromatography. Results of the steady-state fluorescence and 2D NMR experiments show that the recombinant IL-1alpha is in a folded conformation. Far-UV circular dichroism (CD) data suggest that IL-1alpha is an all beta-sheet protein with a beta-barrel architecture. Isothermal titration calorimetry (ITC) experiments show that the recombinant IL-1alpha binds strongly (K(d) approximately 5.6 x 10(-7) M) to S100A13, a calcium binding protein that chaperones the in vivo release of IL-1alpha into the extracellular compartment. Recombinant IL-1alpha was observed to exhibit strong cytostatic effect on human umbilical vascular endothelial cells. The findings of the present study not only pave way for an in-depth structural investigation of the molecular mechanism(s) underlying the non-classical release of IL-1alpha but also provide avenues for the rational design of potent inhibitors against IL-1alpha mediated pathogenesis. 相似文献
170.