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51.
Stefan Sahli Brian Frank W.Bernd Schweizer Franois Diederich Denise Blum‐Kaelin JohannesD. Aebi Hans‐Joachim Bhm Christian Oefner GlennE. Dale 《Helvetica chimica acta》2005,88(4):731-750
A new class of nonpeptidic inhibitors of the ZnII‐dependent metalloprotease neprilysin with IC50 values in the nanomolar activity range (0.034–0.30 μM ) were developed based on structure‐based de novo design (Figs. 1 and 2). The inhibitors feature benzimidazole and imidazo[4,5‐c]pyridine moieties as central scaffolds to undergo H‐bonding to Asn542 and Arg717 and to engage in favorable π‐π stacking interactions with the imidazole ring of His711. The platform is decorated with a thiol vector to coordinate to the ZnII ion and an aryl residue to occupy the hydrophobic S1′ pocket, but lack a substituent for binding in the S2′ pocket, which remains closed by the side chains of Phe106 and Arg110 when not occupied. The enantioselective syntheses of the active compounds (+)‐ 1 , (+)‐ 2 , (+)‐ 25 , and (+)‐ 26 were accomplished using Evans auxiliaries (Schemes 2, 4, and 5). The inhibitors (+)‐ 2 and (+)‐ 26 with an imidazo[4,5‐c]pyridine core are ca. 8 times more active than those with a benzimidazole core ((+)‐ 1 and (+)‐ 25 ) (Table 1). The predicted binding mode was established by X‐ray analysis of the complex of neprilysin with (+)‐ 2 at 2.25‐Å resolution (Fig. 4 and Table 2). The ligand coordinates with its sulfanyl residue to the ZnII ion, and the benzyl residue occupies the S1′ pocket. The 1H‐imidazole moiety of the central scaffold forms the required H‐bonds to the side chains of Asn542 and Arg717. The heterobicyclic platform additionally undergoes π‐π stacking with the side chain of His711 as well as edge‐to‐face‐type interactions with the side chain of Trp693. According to the X‐ray analysis, the substantial advantage in biological activity of the imidazo‐pyridine inhibitors over the benzimidazole ligands arises from favorable interactions of the pyridine N‐atom in the former with the side chain of Arg102. Unexpectedly, replacement of the phenyl group pointing into the deep S1′ pocket by a biphenyl group does not enhance the binding affinity for this class of inhibitors. 相似文献
52.
The gas phase structure of trifluoroethylene sultone, ( 1 ) (3,4,4-trifluoro-1,2-oxathietane-2,2-dioxide) was determined by gas electron diffraction, and the four-membered ring was found to be planar. The following ring parameters (ra distances and ∠α angles with 3σ uncertainties) were derived in the electron diffraction analysis: C? O = 1.41 Å (ass.), C? C = 1.541(18) Å, S? O = 1.652(5) Å, S? C = 1.822(8) Å, S? C? C = 86.2(15)°, C? C? O = 97.1(28)°, C? O? S = 97.5(21)°, and O? S? C = 79.1(8)°. New spectral data (IR, NMR) of 1 , its acyclic isomer FSO2CFHC(O)F ( 2 ), and the related anhydride, FSO2OSO2CFHC(O)F ( 3 ), are reported. New esters containing the fluorosulfonyl function, FSO2CFHC(O)OCH2CF3 ( 4 ), FSO2CFHC(O)OCH2CH = CH2 ( 5 ), and (FSO2CFHC(O)OCH2CH? CH2? )n ( 6 ) have been prepared and characterized. 相似文献
53.
54.
[structure: see text] Four deoxyxylulose phosphate (DXP) analogues were synthesized and evaluated as substrates/inhibitors for methylerythritol phosphate (MEP) synthase. In analogues CF(3)-DXP (1), CF(2)-DXP (2), and CF-DXP (3), the three methyl hydrogens at C1 of DXP were sequentially replaced by fluorine. In the fourth analogue, Et-DXP (4), the methyl group in DXP was replaced by an ethyl moiety. Analogues 1, 2, and 4 were not substrates for MEP synthase under normal catalytic conditions and were instead modest inhibitors with IC(50) values of 2.0, 3.4, and 6.2 mM, respectively. In contrast, 3 was a good substrate (k(cat) = 38 s(-)(1), K(m) = 227 muM) with a turnover rate similar to that of the natural substrate. These results are consistent with a retro-aldol/aldol mechanism rather than an alpha-ketol rearrangement for the enzyme-catalyzed conversion of DXP to MEP. 相似文献
55.
Dale Umbach 《Annals of the Institute of Statistical Mathematics》1981,33(1):81-90
Summary It is desired to estimate a parameter
with the loss function of the formL(θ, a)=W(‖θ−a‖), where
is convex, differentiable, and non-decreasing. With this structure a characterization of Bayes estimators is given. Also
it is noted that if the sample space,
, for the observation,X, is a complete separable metric space then a Bayes estimator exists. 相似文献
56.
ABSTRACTNumerical approximations of the solution of a boundary value problem when an exact solution is not available can be constructed by means of a variety of methods. In this paper, we present a technique that is based on the integral representation of the solution of an elliptic problem and the properties of the associated layer potentials. The procedure is illustrated in application to the mathematical model of bending of plates with transverse shear deformation in a finite domain, in the presence of Dirichlet, Neumann, and Robin conditions prescribed on the boundary. 相似文献
57.
We present a new formulation for the prediction of tyre belt vibrations in the frequency range 0-500 Hz. Our representation includes the effects of belt width, curvature and anisotropy, and also explicitly models the tyre sidewalls. Many of the associated numerical parameters are fixed by physical considerations; the remainder require empirical input. A systematic and general approach to this problem is developed, and illustrated for the specific example of a Goodyear Wrangler tyre. The resulting predictions for the radial response to radial forcing show good correspondence with experiment up to 300 Hz, and satisfactory agreement up to 1 kHz. 相似文献
58.
An efficient and mild method for tetrahydropyranylation of alcohols and their detetrahydropranylation using NH4Cl is described. This protocol provides a useful alternative tetrahydropyranylation of alcohols and their deprotection at different pH. 相似文献
59.
Ylidenemalononitriles are useful reagents, reactive as Michael acceptors2, and in the synthesis of indenones and indanones3, aminonaphthalenes4, and lactones5. Syntheses of these reagents usually involves a typical Knoevenagel reaction between a carbonyl compound and malononitrile, catalyzed by base6. Yields in this condensation vary widely, and are especially poor with hindered ketones and diaryl ketones. For example, Schenck and Finken7 allowed equivalent amounts of benzophenone and malononitrile to react in alcohol for four days, with ammonia as catalyst, and obtained a 13% yield of the corresponding ylidenemalononitrile. Later this was increased by removing water from a refluxing benzene solution of the reactants for 48 hrs3. Although a 68% yield was reported, it was based on unrecovered ketone, and the actual yield was less than 40%. Charles8 has reported the synthesis of the same substance by condensing the 相似文献
60.
Miriam Gochin Landon R. Whitby Aaron H. Phillips Dale L. Boger 《Journal of computer-aided molecular design》2013,27(7):569-582
Due to the inherently flexible nature of a protein–protein interaction surface, it is difficult both to inhibit the association with a small molecule, and to predict how it might bind to the surface. In this study, we have examined small molecules that mediate the interaction between a WWI motif on the C-helix of HIV-1 glycoprotein-41 (gp41) and a deep hydrophobic pocket contained in the interior N-helical trimer. Association between these two components of gp41 leads to virus–cell and cell–cell fusion, which could be abrogated in the presence of an inhibitor that binds tightly in the pocket. We have studied a comprehensive combinatorial library of α-helical peptidomimetics, and found that compounds with strongly hydrophobic side chains had the highest affinity. Computational docking studies produced multiple possible binding modes due to the flexibility of both the binding site and the peptidomimetic compounds. We applied a transferred paramagnetic relaxation enhancement experiment to two selected members of the library, and showed that addition of a few experimental constraints enabled definitive identification of unique binding poses. Computational docking results were extremely sensitive to side chain conformations, and slight variations could preclude observation of the experimentally validated poses. Different receptor structures were required for docking simulations to sample the correct pose for the two compounds. The study demonstrated the sensitivity of predicted poses to receptor structure and indicated the importance of experimental verification when docking to a malleable protein–protein interaction surface. 相似文献