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排序方式: 共有356条查询结果,搜索用时 15 毫秒
71.
72.
Istyastono EP Nijmeijer S Lim HD van de Stolpe A Roumen L Kooistra AJ Vischer HF de Esch IJ Leurs R de Graaf C 《Journal of medicinal chemistry》2011,54(23):8136-8147
The histamine H(4) receptor (H(4)R) is a G protein-coupled receptor (GPCR) that plays an important role in inflammation. Similar to the homologous histamine H(3) receptor (H(3)R), two acidic residues in the H(4)R binding pocket, D(3.32) and E(5.46), act as essential hydrogen bond acceptors of positively ionizable hydrogen bond donors in H(4)R ligands. Given the symmetric distribution of these complementary pharmacophore features in H(4)R and its ligands, different alternative ligand binding mode hypotheses have been proposed. The current study focuses on the elucidation of the molecular determinants of H(4)R-ligand binding modes by combining (3D) quantitative structure-activity relationship (QSAR), protein homology modeling, molecular dynamics simulations, and site-directed mutagenesis studies. We have designed and synthesized a series of clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) derivatives to investigate H(4)R-ligand interactions and ligand binding orientations. Interestingly, our studies indicate that clobenpropit (2) itself can bind to H(4)R in two distinct binding modes, while the addition of a cyclohexyl group to the clobenpropit isothiourea moiety allows VUF5228 (5) to adopt only one specific binding mode in the H(4)R binding pocket. Our ligand-steered, experimentally supported protein modeling method gives new insights into ligand recognition by H(4)R and can be used as a general approach to elucidate the structure of protein-ligand complexes. 相似文献
73.
de Graaf C Kooistra AJ Vischer HF Katritch V Kuijer M Shiroishi M Iwata S Shimamura T Stevens RC de Esch IJ Leurs R 《Journal of medicinal chemistry》2011,54(23):8195-8206
The recent crystal structure determinations of druggable class A G protein-coupled receptors (GPCRs) have opened up excellent opportunities in structure-based ligand discovery for this pharmaceutically important protein family. We have developed and validated a customized structure-based virtual fragment screening protocol against the recently determined human histamine H(1) receptor (H(1)R) crystal structure. The method combines molecular docking simulations with a protein-ligand interaction fingerprint (IFP) scoring method. The optimized in silico screening approach was successfully applied to identify a chemically diverse set of novel fragment-like (≤22 heavy atoms) H(1)R ligands with an exceptionally high hit rate of 73%. Of the 26 tested fragments, 19 compounds had affinities ranging from 10 μM to 6 nM. The current study shows the potential of in silico screening against GPCR crystal structures to explore novel, fragment-like GPCR ligand space. 相似文献
74.
Setiawati E Deniati SH Yunaidi DA Handayani LR Santoso ID Arland JA Setiawati A Lian LY 《Arzneimittel-Forschung》2011,61(4):234-238
The present study was performed to compare the bioavailability of two perindopril erbumine (CAS 107133-36-8) 4 mg tablet formulations (test formulation and reference formulation). This study was a randomized, single-blind, two-period, two-sequence cross-over study which included 20 healthy adult male and female subjects under fasting conditions. In this study, one subject withdrew from the study and one reserve subject did not appear at both periods. The pharmacokinetic parameters were assessed based on the concentrations of perindopril (CAS 82834-16-0) and perindoprilat (CAS 95153-31-4) because perindopril has litte pharmacologic activity until hydrolized in the liver into its active metabolite, perindoprilat. The blood samples from 18 subjects were analyzed for plasma concentrations of perindopril and perindoprilat. In each of the two study periods (separated by a washout of three weeks) a single dose of test or reference drug was administered. Plasma concentrations of the drug were determined by LC-MS/MS method. The pharmacokinetic parameters assessed in this study were area under the plasma concentration-time curve from time zero to 192 h (AUC), area under the plasma concentration-time curve from time zero to infinity (AUCinf), the peak plasma concentration of the drug (Cmax time needed to achieve the peak plasma concentration (tmax), and the elimination half-life (t(1/2)). The geometric mean ratios (90% CI) of the test drug/reference drug for perindopril and perindoprilat were 106.59% (92.97-122.20%) and 100.56% (94.11-107.46%) for AUC,, 106.64% (93.39-121.77%) and 100.88% (95.30-106.80%) for AUCinfo, and 101.23% (87.39-117.27%) and 99.30% (90.42-109.05%) for Cmax, respectively. The 90% confidence intervals calculated for AUCt and Cmax of perindopril and perindoprilat were within the standard bioequivalence range (80-125% for AUC and Cmax). It was concluded that the two perindopril erbumine tablets (test and reference drug) were bioequivalent in terms of the rate and extent of absorption. 相似文献
75.
Istyastono EP de Graaf C de Esch IJ Leurs R 《Current topics in medicinal chemistry》2011,11(6):661-679
The deorphanization of the histamine H? receptor (H?R) has led to a significant number of scientific publications and patent applications. Whereas some histamine H?, H? and H? receptor ligands were found to have significant affinity for H?R, several agonists and antagonists with high affinity for H?R and selectivity over the other histamine receptors were successfully designed and synthesized. Moreover, site-directed mutation studies on H?R have been performed and reveal detailed information on receptor-ligand interactions. This review will focus on the most important H?R ligand scaffolds and their structure-activity relationships and selectivity over other histamine receptors and specific H?R functional activity. Experimental data are used to construct and validate high resolution three-dimensional receptor-ligand models and, vice versa, in silico models are used to design and rationalize experimental studies to probe receptor-ligand interactions. 相似文献
76.
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78.
We demonstrate that doubly-resonant coherent anti-Stokes Raman scattering can provide enhanced and highly specific contrast for molecules containing unique Raman-active small molecular groups. This combination provides contrast for molecules that can otherwise be difficult to discriminate by Raman spectroscopy. Here, human monocytes were incubated with either deuterated oleic acid or 17-octadecynoic acid (a fatty acid with an end terminal acetylene group). The carbon-deuterium stretching vibration of the deuterated fatty acid, as well as the unique alkyne stretching vibration of the alkyne-containing fatty acid, were used to provide contrast for these exogenous free fatty acids. The combination of these unique modes with the common aliphatic carbon-hydrogen stretching vibration inherent to all fatty acid allowed for doubly-resonant detection of these unique molecules and enabled us to detect the presence of these lipids in areas within a cell where each molecular resonance by itself did not generate sufficient signal. 相似文献
79.
80.
Chris P.H. Lexis MD Iwan C.C. van der Horst MD PhD Braim M. Rahel MD PhD Monique A.S. Lexis MSc Marthe A. Kampinga MD Youlan L. Gu MD Bart J.G.L. de Smet MD PhD Felix Zijlstra MD PhD 《Catheterization and cardiovascular interventions》2011,77(4):484-491
Objectives: This study evaluated the impact of a chronic total occlusion (CTO) in a non‐infarct related coronary artery (IRA) on markers of reperfusion, infarct size, and long‐term cardiac mortality in patients with ST‐elevation myocardial infarction (STEMI). Background: A concurrent CTO in STEMI patients has been associated with impaired left ventricular function and outcome. However, the impact on markers of reperfusion is unknown. Methods: All 1,071 STEMI patients included in the TAPAS‐trial between January 2005 and December 2006 were used for this substudy. Endpoints were the association between a CTO in a non‐IRA and myocardial blush grade (MBG) of the IRA, ST‐segment elevation resolution (STR), enzymatic infarct size, and clinical outcome. Results: A total of 90 patients (8.4%) had a CTO. MBG 0 or 1 occurred more often in the CTO group (34.2% versus 20.6% (Odds Ratio [OR] 2.00, 95% confidence interval [CI]: 1.22–3.23, P = 0.006)). Incomplete STR occurred more often in the CTO group, (63.6% versus 48.2% [OR 1.96, 95% CI: 1.22–3.13, P = 0.005]). Median level of maximal myocardial‐band of creatinin kinase (CK‐MB) in the CTO group was 75 μg/l (IQR 28‐136) and 51 μg/l (IQR 18–97) in the no‐CTO group (P = 0.021). The presence of a CTO in a non‐IRA in STEMI patients was an independent risk factor for cardiac mortality (HR 2.41, 95% CI: 1.26–4.61, P = 0.008) at 25 months follow‐up. Conclusion: A CTO in a non‐IRA is associated with impaired reperfusion markers and impaired long‐term outcome in STEMI patients. © 2010 Wiley‐Liss, Inc. 相似文献