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151.
Jian-Liang Zhou Jing-Jing An Ping Li Hui-Jun Li Yan Jiang Jie-Fei Cheng 《Journal of chromatography. A》2009,1216(12):2394-2403
We present herein a novel bioseparation/chemical analysis strategy for protein–ligand screening and affinity ranking in compound mixtures, designed to increase screening rates and improve sensitivity and ruggedness in performance. The strategy is carried out by combining on-line two-dimensional turbulent flow chromatography (2D-TFC) with liquid chromatography–mass spectrometry (LC–MS), and accomplished through the following steps: (1) a reversed-phase TFC stage to separate the protein/ligand complex from the unbound free molecules, (2) an on-line dissociation process to release the bound ligands from the complexes, and (3) a second mixed-mode cation-exchange/reversed-phase TFC stage to trap the bound ligands and to remove the proteins and salts, followed by LC–MS analysis for identification and determination of the binding affinities. The technique can implement an ultra-fast isolation of protein/ligand complex with the retention time of a complex peak in about 5 s, and on-line prepare the “clean” sample to be directly compatible with the LC–MS analysis. The improvement in performance of this 2D-TFC/LC–MS approach over the conventional approach has been demonstrated by determining affinity-selected ligands of the target proteins acetylcholinesterase and butyrylcholinesterase from a small library with known binding affinities and a steroidal alkaloid library composed of structurally similar compounds. Our results show that 2D-TFC/LC–MS is a generic and efficient tool for high-throughput screening of ligands with low-to-high binding affinities, and structure-activity relationship evaluation. 相似文献
152.
Over the past 8 years, we have developed, refined and applied a fragment based discovery approach to a range of protein targets.
Here we report computational analyses of various aspects of our fragment library and the results obtained for fragment screening.
We reinforce the finding of others that the experimentally observed hit rate for screening fragments can be related to a computationally
defined druggability index for the target. In general, the physicochemical properties of the fragment hits display the same
profile as the library, as is expected for a truly diverse library which probes the relevant chemical space. An analysis of
the fragment hits against various protein classes has shown that the physicochemical properties of the fragments are complementary
to the properties of the target binding site. The effectiveness of some fragments appears to be achieved by an appropriate
mix of pharmacophore features and enhanced aromaticity, with hydrophobic interactions playing an important role. The analysis
emphasizes that it is possible to identify small fragments that are specific for different binding sites. To conclude, we
discuss how the results could inform further development and improvement of our fragment library.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
153.
Ragothaman Yennamalli Naidu Subbarao Thorsten Kampmann Ross P. McGeary Paul R. Young Bostjan Kobe 《Journal of computer-aided molecular design》2009,23(6):333-341
Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment
to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational
changes in the E protein and is an essential step in the virus life cycle. In this study, we analyzed the pre-fusion and post-fusion
structures of the dengue virus E protein to identify potential novel sites that could bind small molecules, which could interfere
with the conformational transitions that mediate the fusion process. We used an in silico virtual screening approach combining
three different docking algorithms (DOCK, GOLD and FlexX) to identify compounds that are likely to bind to these sites. Seven
structurally diverse molecules were selected to test experimentally for inhibition of dengue virus propagation. The best compound
showed an IC50 in the micromolar range against dengue virus type 2.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
154.
Markus H. J. Seifert 《Journal of computer-aided molecular design》2009,23(9):633-644
Target-specific optimization of scoring functions for protein–ligand docking is an effective method for significantly improving
the discrimination of active and inactive molecules in virtual screening applications. Its applicability, however, is limited
due to the narrow focus on, e.g., single protein structures. Using an ensemble of protein kinase structures, the publically
available directory of useful decoys ligand dataset, and a novel multi-factorial optimization procedure, it is shown here
that scoring functions can be tuned to multiple targets of a target class simultaneously. This leads to an improved robustness
of the resulting scoring function parameters. Extensive validation experiments clearly demonstrate that (1) virtual screening
performance for kinases improves significantly; (2) variations in database content affect this kind of machine-learning strategy
to a lesser extent than binary QSAR models, and (3) the reweighting of interaction types is of particular importance for improved
screening performance.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
155.
Shereena M. Arif John D. Holliday Peter Willett 《Journal of computer-aided molecular design》2009,23(9):655-668
Current systems for similarity-based virtual screening use similarity measures in which all the fragments in a fingerprint
contribute equally to the calculation of structural similarity. This paper discusses the weighting of fragments on the basis
of their frequencies of occurrence in molecules. Extensive experiments with sets of active molecules from the MDL Drug Data Report and the World of Molecular Bioactivity databases, using fingerprints encoding Tripos holograms, Pipeline Pilot ECFC_4 circular substructures and Sunset Molecular
keys, demonstrate clearly that frequency-based screening is generally more effective than conventional, unweighted screening.
The results suggest that standardising the raw occurrence frequencies by taking the square root of the frequencies will maximise
the effectiveness of virtual screening. An upper-bound analysis shows the complex interactions that can take place between
representations, weighting schemes and similarity coefficients when similarity measures are computed, and provides a rationalisation
of the relative performance of the various weighting schemes. 相似文献
156.
Long Yi Heyang Li Lu Sun Liangliang Liu Caihong Zhang Zhen Xi Prof. Dr. 《Angewandte Chemie (International ed. in English)》2009,48(22):4034-4037
Fast detection of cellular thiols in aqueous medium was achieved using a newly developed fluorescence probe (see picture). Based on this probe, a high‐throughput fluorescence assay for glutathione reductase was developed.
157.
Luis M. Fidalgo Graeme Whyte Dr. Brandon T. Ruotolo Dr. Justin L. P. Benesch Dr. Florian Stengel Chris Abell Prof. Carol V. Robinson Prof. Wilhelm T. S. Huck Prof. 《Angewandte Chemie (International ed. in English)》2009,48(20):3665-3668
Fully integrated : Mass spectrometry has been integrated into a detection scheme for microdroplets that are created within microfluidic channels (see picture, scale bar 200 μm). This technique allows droplets to be identified based on the compounds they contain, and combines fluorescence screening with MS analysis. These experiments indicate how similar approaches can be applied to the ambitious goals of on‐chip protein evolution and chemical synthesis.
158.
Laurent A. Baumes Dr. Manuel Moliner Dr. Avelino Corma Dr. 《Chemistry (Weinheim an der Bergstrasse, Germany)》2009,15(17):4258-4269
Finding a clear route to new structures : The design of an adaptable time warping (ATW) methodology (see figure) for automatically, quickly, and reliably deciphering X‐ray diffraction patterns is described.
159.
160.
T. Portolés J. V. Sancho F. Hernández A. Newton P. Hancock 《Journal of mass spectrometry : JMS》2010,45(8):926-936
The potential applications of a new atmospheric pressure source for GC‐MS analysis have been investigated in this work. A list of around 100 GC‐amenable pesticides, which includes organochlorine, organophosphorus and organonitrogenated compounds, has been used to evaluate their behavior in the new source. Favoring the major formation of the molecular ion in the source has been the main goal due to the wide‐scope screening possibilities that this fact brings in comparison with the traditional, highly fragmented electron ionization spectra. Thus, the addition of water as modifier has been tested as a way to promote the generation of protonated molecules. Pesticides investigated have been classified into six groups according to their ionization/fragmentation behavior. Four of them are characterized by the abundant formation of the protonated molecule in the atmospheric pressure source, mostly being the base peak of the spectrum. These results show that wide‐scope screening could be easily performed with this source by investigating the presence of the protonated molecule ion, MH+. The developed procedure has been applied to pesticide screening in different food samples (nectarine, orange and spinach) and it has allowed the presence of several pesticides to be confirmed such as chlorpyriphos ethyl, deltamethrin and endosulfan sulfate. The availability of a quadrupole time‐of‐flight instrument made it feasible to perform additional MS/MS experiments for both standards and samples to go further in the confirmation of the identity of the detected compounds. Results shown in this paper have been obtained using a prototype source which exhibits promising features that could be applied to other analytical problems apart from those illustrated in this work. Copyright © 2010 John Wiley & Sons, Ltd. 相似文献