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1.
Circularly polarized luminescence of Sm (III) and Eu (III) complexes with chiral ligand (R/S)‐BINAPO
Luminescent lanthanide (III) ions have been exploited for circularly polarized luminescence (CPL) for decades. However, very few of these studies have involved chiral samarium (III) complexes. Complexes are prepared by mixing axial chiral ligands (R/S))‐2,2’‐bis(diphenylphosphoryl)‐1,1′‐binaphthyl (BINAPO) with europium and samarium Tris (trifluoromethane sulfonate) (Eu (OTf)3 and Sm (OTf)3). Luminescence‐based titration shows that the complex formed is Ln((R/S)‐BINAPO)2(OTf)3, where Ln = Eu or Sm. The CPL spectra are reported for Eu((R/S)‐BINAPO)2(OTf)3 and Sm((R/S)‐BINAPO)2(OTf)3. The sign of the dissymmetry factors, gem, was dependent upon the chirality of the BINAPO ligand, and the magnitudes were relatively large. Of all of the complexes in this study, Sm((S)‐BINAPO)2(OTf)3 has the largest gem = 0.272, which is one of the largest recorded for a chiral Sm3+ complex. A theoretical three‐dimensional structural model of the complex that is consistent with the experimental observations is developed and refined. This report also shows that (R/S)‐BINAPO are the only reported ligands where gem (Sm3+) > gem (Eu3+). 相似文献
2.
Franciskovich JB Masters JJ Weber WW Klimkowski VJ Chouinard M Sipes PR Johnson LM Snyder DW Chastain MK Craft TJ Towner RD Gifford-Moore DS Froelich LL Smallwood JK Foster RS Smith GF Liebeschuetz JW Murray CW Young SC 《Bioorganic & medicinal chemistry letters》2007,17(24):6910-6913
Several P4 domain derivatives of the general d-phenylglycinamide-based scaffold (2) were synthesized and evaluated for their ability to bind to the serine protease factor Xa. Some of the more potent compounds were evaluated for their anticoagulant effects in vitro. A select subset containing various P1 indole constructs was further evaluated for their pharmacokinetic properties after oral administration to rats. 相似文献
3.
Franciskovich JB Masters JJ Tinsley JM Craft TJ Froelich LL Gifford-Moore DS Klimkowski VJ Smallwood JK Smith GF Smith T Towner RR Weir LC Wiley MR 《Bioorganic & medicinal chemistry letters》2005,15(21):4838-4841
Several non-amidino S1 derivatives of the 1,2-diaminobenzene-based scaffold (4) were synthesized and evaluated for their ability to bind to the active site and inhibit the human protease factor Xa. A subset of these compounds were also evaluated for their anticoagulant effects in human plasma as measured by prothrombin time (PT). 相似文献
4.
The crystal structure of human alpha-thrombin complexed with LY178550, a nonpeptidyl, active site-directed inhibitor. 下载免费PDF全文
N. Y. Chirgadze D. J. Sall V. J. Klimkowski D. K. Clawson S. L. Briggs R. Hermann G. F. Smith D. S. Gifford-Moore J. P. Wery 《Protein science : a publication of the Protein Society》1997,6(7):1412-1417
The crystal structure of human alpha-thrombin in complex with LY178550, a nonpeptidyl, active site-directed inhibitor, has been solved to 2.07 A resolution by the method of X-ray crystallography. The final model of the complex has a crystallographic R-value of 21.5% (Rfree = 23.1%) with 0.014 A and 2.4 degrees standard deviation from ideal bond lengths and angles, respectively. Well-defined electron density was observed for the inhibitor in the active site. The inhibitor binds to the active site in an L-shaped manner, mimicking the bound conformation of the tripeptide arginal series of thrombin inhibitors (Chirgadze NY et al., 1992, American Crystallographic Association Meeting 20: 116 [Abstr. PB311]). The basic amidine of LY178550 forms a salt bridge with Asp 189 within the specificity pocket, while the 4-benzylpiperidine side chain engages in a number of hydrophobic interactions at the S2 and S3 binding sites. The inhibitor does not interact in any fashion with the active site sequence Ser 214-Gly 216, as occurs with many of the inhibitors studied previously. The indole N-H of the inhibitor forms a hydrogen bond to the gamma-oxygen of the catalytic serine (Ser 195). 相似文献
5.
Sheehan SM Mest HJ Watson BM Klimkowski VJ Timm DE Cauvin A Parsons SH Shi Q Canada EJ Wiley MR Ruehter G Evers B Petersen S Blaszczak LC Pulley SR Margolis BJ Wishart GN Renson B Hankotius D Mohr M Zechel JC Michael Kalbfleisch J Dingess-Hammond EA Boelke A Weichert AG 《Bioorganic & medicinal chemistry letters》2007,17(6):1765-1768
A series of non-covalent inhibitors of the serine protease dipeptidyl peptidase IV (DPP-IV) were found to adopt a U-shaped binding conformation in X-ray co-crystallization studies. Remarkably, Tyr547 undergoes a 70 degrees side-chain rotation to accommodate the inhibitor and allows access to a previously unexposed area of the protein backbone for hydrogen bonding. 相似文献
6.
Klimkowski VJ Watson BM Wiley MR Liebeschuetz J Franciskovich JB Marimuthu J Bastian JA Sall DJ Smallwood JK Chirgadze NY Smith GF Foster RS Craft T Sipes P Chastain M Sheehan SM 《Bioorganic & medicinal chemistry letters》2007,17(21):5801-5805
Analogs to a series of D-phenylglycinamide-derived factor Xa inhibitors were discovered. It was found that the S4 amide linkage can be replaced with an ether linkage to reduce the peptide character of the molecules and that this substitution leads to an increase in binding affinity that is not predicted based on modeling. Inhibitors which incorporate ether, amino, or alkyl S4 linkage motifs exhibit similar levels of binding affinity and also demonstrate potent in vitro functional activity, however, binding affinity in this series is strongly dependent on the nature of the S1 binding element. 相似文献
7.
Zhang M Bailey DL Bastian JA Briggs SL Chirgadze NY Clawson DK Denney ML Gifford-Moore DS Harper RW Johnson LM Klimkowski VJ Kohn TJ Lin HS McCowan JR Richett ME Sall DJ Smith AJ Smith GF Snyder DW Takeuchi K Utterback BG Yan SC 《Bioorganic & medicinal chemistry letters》1999,9(5):775-780
Potent, subnanomolar thrombin inhibitors 4, 5, and 6 are developed through side chain optimization of novel, benzo[b]thiophene-based small organic entities 2 and 3 and through SAR additivity studies of the new structural elements identified. X-ray crystallographic studies of 4b-thrombin complex revealed a hydrophobic and an electrostatic interaction of these new elements with thrombin at the S2 and S3 binding sites. In vitro and in vivo pharmacological studies showed that 4, 5, and 6 are potent anticoagulants in human plasma with demonstrated antithrombotic efficacy in a rat model of thrombosis. 相似文献
8.
Timothy B. Durham James L. Toth Valentine J. Klimkowski Julia X. C. Cao Angela M. Siesky Jesline Alexander-Chacko Ginger Y. Wu Jeffrey T. Dixon James E. McGee Yong Wang Sherry Y. Guo Rachel Nicole Cavitt John Schindler Stefan J. Thibodeaux Nathan A. Calvert Michael J. Coghlan Dana K. Sindelar Michael Christe Vladislav V. Kiselyov M. Dodson Michael Kyle W. Sloop 《The Journal of biological chemistry》2015,290(33):20044-20059
Insulin-degrading enzyme (IDE, insulysin) is the best characterized catabolic enzyme implicated in proteolysis of insulin. Recently, a peptide inhibitor of IDE has been shown to affect levels of insulin, amylin, and glucagon in vivo. However, IDE−/− mice display variable phenotypes relating to fasting plasma insulin levels, glucose tolerance, and insulin sensitivity depending on the cohort and age of animals. Here, we interrogated the importance of IDE-mediated catabolism on insulin clearance in vivo. Using a structure-based design, we linked two newly identified ligands binding at unique IDE exosites together to construct a potent series of novel inhibitors. These compounds do not interact with the catalytic zinc of the protease. Because one of these inhibitors (NTE-1) was determined to have pharmacokinetic properties sufficient to sustain plasma levels >50 times its IDE IC50 value, studies in rodents were conducted. In oral glucose tolerance tests with diet-induced obese mice, NTE-1 treatment improved the glucose excursion. Yet in insulin tolerance tests and euglycemic clamp experiments, NTE-1 did not enhance insulin action or increase plasma insulin levels. Importantly, IDE inhibition with NTE-1 did result in elevated plasma amylin levels, suggesting the in vivo role of IDE action on amylin may be more significant than an effect on insulin. Furthermore, using the inhibitors described in this report, we demonstrate that in HEK cells IDE has little impact on insulin clearance. In total, evidence from our studies supports a minimal role for IDE in insulin metabolism in vivo and suggests IDE may be more important in helping regulate amylin clearance. 相似文献
9.
Mendel D Marquart AL Joseph S Waid P Yee YK Tebbe AL Ratz AM Herron DK Goodson T Masters JJ Franciskovich JB Tinsley JM Wiley MR Weir LC Kyle JA Klimkowski VJ Smith GF Towner RD Froelich LL Buben J Craft TJ 《Bioorganic & medicinal chemistry letters》2007,17(17):4832-4836
SAR about the B-ring of a series of N(2)-aroyl anthranilamide factor Xa (fXa) inhibitors is described. B-ring o-aminoalkylether and B-ring p-amine probes of the S1' and S4 sites, respectively, afforded picomolar fXa inhibitors that performed well in in vitro anticoagulation assays. 相似文献
10.
Catechol 2, 3-dioxygenase is present in several types of bacteria and undergoes degradation of environmental pollutants through
an important key biochemical pathways. Specifically, this enzyme cleaves aromatic rings of several environmental pollutants such
as toluene, xylene, naphthalene and biphenyl derivatives. Hence, the importance of Catechol 2, 3-dioxygenase and its role in the
degradation of environmental pollutants made us to predict the three-dimensional structure of Catechol 2, 3-dioxygenase from
Burkholderia cepacia. The 10ns molecular dynamics simulation was carried out to check the stability of the modeled Catechol 2, 3-
dioxygenase. The results show that the model was energetically stable, and it attains their equilibrium within 2000 ps of production
MD run. The docking of various petroleum hydrocarbons into the Catechol 2,3-dioxygenase reveals that the benzene, O-xylene,
Toluene, Fluorene, Naphthalene, Carbazol, Pyrene, Dibenzothiophene, Anthracene, Phenanthrene, Biphenyl makes strong
hydrogen bond and Van der waals interaction with the active site residues of H150, L152, W198, H206, H220, H252, I254, T255,
Y261, E271, L276 and F309. Free energy of binding and estimated inhibition constant of these compounds demonstrates that they
are energetically stable in their binding cavity. Chrysene shows positive energy of binding in the active site atom of Fe. Except
Pyrene all the substrates made close contact with Fe atom by the distance ranges from 1.67 to 2.43 Å. In addition to that, the above
mentioned substrate except pyrene all other made π-π stacking interaction with H252 by the distance ranges from 3.40 to 3.90 Å.
All these docking results reveal that, except Chrysene all other substrate has good free energy of binding to hold enough in the
active site and makes strong VdW interaction with Catechol-2,3-dioxygenase. These results suggest that, the enzyme is capable of
catalyzing the above-mentioned substrate. 相似文献