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241.
242.
EmmanuelA. Meyer Nicola Donati Marine Guillot W.Bernd Schweizer Franois Diederich Bernhard Stengl Ruth Brenk Klaus Reuter Gerhard Klebe 《Helvetica chimica acta》2006,89(4):573-597
This paper describes the rational design, synthesis, and biological evaluation of a new generation of inhibitors of the bacterial enzyme tRNA‐guanine transglycosylase (TGT), which has been identified as a new target in the fight against bacillary dysentery (Shigellosis). The enzyme catalyzes the exchange of guanine in the anticodon wobble position of tRNA by the modified base preQ1, a guanine derivative, according to a ping‐pong mechanism involving a covalent TGT‐tRNA intermediate (Fig. 2). Based on computer modeling (Fig. 3), lin‐benzoguanine (6‐aminoimidazol[4,5‐g]quinazolin‐8(7H)‐one ( 2 )) was selected as an extended central scaffold, to form up to seven in‐plane intermolecular H‐bonds with the protein while sandwiching between Tyr106 and Met260. Versatile synthetic protocols were developed for the synthesis of 2 , and derivatives with phenyl, benzyl, and 2‐phenylethyl side chains (i.e., 16, 17a , and 12a, 12b, 13, 17 , resp.) to reach into the lipophilic pocket lined by Val282, Val45, and Leu68 (Schemes 1–3). To account for the limited solubility of the new ligands and in consequence of a recently developed detailed understanding of the mechanism of TGT catalysis (Fig. 2), the enzyme kinetic assay was completely redesigned, providing competitive (Kic) and uncompetitive (Kiu) inhibition constants with respect to tRNA binding by TGT. The modifications of the various parameters in the new assay are described in detail. Binding affinities of the new inhibitors were found to be in the single‐digit micromolar range (Kic values, Fig. 8). Decoration of the lin‐benzoguanine scaffold with lipophilic residues only gave a modest improvement in biological activity which was explained on structural grounds with the help of four crystal structures (Fig. 10) obtained by soaking the protein with inhibitors 2 and 12a – 12c . Both biochemical and biostructural analyses reported in this paper provide a fertile basis for the development of more potent future generations of TGT inhibitors. 相似文献
243.
Breccia P Van Gool M Pérez-Fernández R Martín-Santamaría S Gago F Prados P de Mendoza J 《Journal of the American Chemical Society》2003,125(27):8270-8284
A number of artificial carriers for the transport of zwitterionic aromatic amino acids across bulk model membranes (U-tube type) have been prepared and evaluated. 1,2-Dichloroethane and dichloromethane were employed in the organic phase. All compounds are based on a bicyclic chiral guanidinium scaffold that ideally complements the carboxylate function. The guanidinium central moiety was attached to crown ethers or lasalocid A as specific subunits for ammonium recognition as well as to aromatic or hydrophobic residues to evaluate their potential interaction with the side chains of the guest amino acids. The subunits were linked to the guanidinium through ester or amide connectors. Amides were found to be better carriers than esters, though less enantioselective. On the other hand, crown ethers were superior to lasalocid derivatives. As expected, transport rates were dependent on the carrier concentration in the liquid membrane. Reciprocally, enantioselectivities were much higher at lower carrier concentrations. The results show that our previously proposed three-point binding model (J. Am. Chem. Soc. 1992, 114, 1511-1512), involving the participation of the aromatic or hydrophobic residue to interact with the side chains of the amino acid guest, is unnecessary to explain the high enantioselectivities observed. Molecular dynamics fully support a two-point model involving only the guanidinium and crown ether moieties. These molecules constitute the first examples of chiral selectors for underivatized amino acids acting as carriers under neutral conditions. 相似文献
244.
Nicholas A. Barnes Stephen M. Godfrey Ruth T.A. Halton Imrana Mushtaq Simon Parsons Robin G. Pritchard Mark Sadler 《Polyhedron》2007
Structural and spectroscopic data on the series of compounds “PhSeX”, where X = Cl, CN or SCN, are reported and compared with previously reported data on “PhSeX” systems (X = Br and I). The chloro-compound displays a “square” motif, Ph4Se4Cl4, in the solid state, linked by long Se–Se bonds [2.993(3)–3.035(3) Å], and forms a loosely held network of Se4 and Cl4 squares in its extended structure. In contrast, the pseudohalogen derivatives, PhSeCN and PhSeSCN, consist of essentially monomeric units, which form chains held together by weak Se?N interactions in the solid state. These Se?N interactions are much shorter in PhSeCN, 3.023(3)–3.065(4) Å, than in PhSeSCN, 3.348(4) Å. Weaker Se?N contacts are also present between the chains. The structure of PhSeSCN described here is the first reported crystallographic study of a selenium thiocyanate compound. Spectroscopic studies suggest that all three compounds exist as monomers in solution. The results reported herein illustrate the subtle differences in the solid-state structures of PhSeX compounds. 相似文献
245.
Bacha PA Gruver HS Den Hartog BK Tamura SY Nutt RF 《Journal of chemical information and computer sciences》2002,42(5):1104-1111
A public bacterial mutagenicity database was classified into 2-D structural families using a set of specific algorithms and clustering techniques that find overlapping classes of compounds based upon chemical substructures. Structure-activity relationships were learned from the biological activity of the compounds within each class and used to identify rules that define substructures potentially responsible for mutagenic activity. In addition, this method of analysis was used to compare the pharmacologically relevant substructure of test compounds with their potential toxic substructures making this a potentially valuable in silico profiling tool for lead selection and optimization. 相似文献
246.
247.
Ruth Charney 《代数通讯》2013,41(17-18):2081-2123
248.
249.