全文获取类型
收费全文 | 2407篇 |
免费 | 168篇 |
国内免费 | 78篇 |
专业分类
2653篇 |
出版年
2024年 | 3篇 |
2023年 | 23篇 |
2022年 | 43篇 |
2021年 | 48篇 |
2020年 | 56篇 |
2019年 | 86篇 |
2018年 | 93篇 |
2017年 | 58篇 |
2016年 | 53篇 |
2015年 | 69篇 |
2014年 | 122篇 |
2013年 | 181篇 |
2012年 | 87篇 |
2011年 | 196篇 |
2010年 | 133篇 |
2009年 | 160篇 |
2008年 | 156篇 |
2007年 | 150篇 |
2006年 | 137篇 |
2005年 | 140篇 |
2004年 | 119篇 |
2003年 | 88篇 |
2002年 | 82篇 |
2001年 | 35篇 |
2000年 | 42篇 |
1999年 | 32篇 |
1998年 | 37篇 |
1997年 | 26篇 |
1996年 | 25篇 |
1995年 | 31篇 |
1994年 | 14篇 |
1993年 | 10篇 |
1992年 | 14篇 |
1991年 | 16篇 |
1990年 | 2篇 |
1989年 | 12篇 |
1988年 | 7篇 |
1987年 | 7篇 |
1986年 | 3篇 |
1985年 | 8篇 |
1984年 | 14篇 |
1983年 | 7篇 |
1982年 | 5篇 |
1981年 | 5篇 |
1980年 | 5篇 |
1979年 | 3篇 |
1977年 | 3篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1973年 | 2篇 |
排序方式: 共有2653条查询结果,搜索用时 0 毫秒
1.
(+)-2,9 alpha-Dimethyl-5-(m-hydroxyphenyl)morphan is the only phenylmorphan analog whose affinity for opioid kappa-receptors is greater than its affinity for opioid mu-receptors. Pharmacologically, the compound is a pure opioid antagonist devoid of agonist activity in in vivo assays of antinociception. The absolute configuration of the compound has been determined to be (1R,5S,9R) from an X-ray crystallographic study of the chloride salt. Thus, the absolute configuration corresponds to that of the atypical opioid agonist (-)-phenylmorphan while the weak atypical agonist (-)-2,9 alpha-dimethyl-5-(m- hydroxyphenyl)morphan corresponds to the potent morphine-like (+)-phenylmorphan. The preferred orientations of the phenyl ring for the two stereoisomers were determined using the molecular mechanics program MM2-87 and found to vary from that of the two parent compounds. The atypical properties of the two 9 alpha-methyl analogs is consistent with an opioid ligand model which proposes that morphine-like properties require a particular range of phenyl orientations. There was good agreement between the structure obtained from X-ray crystallography and computed with the MM2-87 program. 相似文献
2.
A computer algorithm, CLIX, capable of searching a crystallographic data-base of small molecules for candidates which have both steric and chemical likelihood of binding a protein of known three-dimensional structure is presented. The algorithm is a significant advance over previous strategies which consider solely steric or chemical requirements for binding. The algorithm is shown to be capable of predicting the correct binding geometry of sialic acid to a mutant influenza-virus hemagglutinin and of proposing a number of potential new ligands to this protein. 相似文献
3.
Kenneth A. Marx Ray Kruger Michael J. Clarke 《Molecular and cellular biochemistry》1989,86(2):155-162
The goal of this study is to establish the nature of pentammineruthenium(III) binding to DNA in intact mouse liver nuclei. Also, we wish to determine whether the nucleosomal organization of mouse chromatin has a substantial effect on the relative Ru(III) binding levels of internucleosomal and nucleosomal core DNA. These questions are important because ammineruthenium compounds share chemical and biological properties with the cis-dichlorodiammineplatinum(II) or cisplatin chemotherapeutic agent. Therefore, they represent a potential class of new chemotherapeutic agents. We find that in intact nuclei the predominant DNA binding site for pentammineruthenium(II), followed by air oxidation to pentammineruthenium(III), is N-7 guanine, as is the case with cisplatin. Also, the Ru(III) distribution between internucleosomal and nucleosomal core DNA was found to be nearly identical as probed with three non-specific deoxyribonucleases. 相似文献
4.
Peter Mitchell 《Bioscience reports》1991,11(6):297-346
Chemical transformations, like osmotic translocations, are transport processes when looked at in detail. In chemiosmotic systems, the pathways of specific ligand conduction are spatially orientated through osmoenzymes and porters in which the actions of chemical group, electron and solute transfer occur as vectorial (or higher tensorial order) diffusion processes down gradients of total potential energy that represent real spatially-directed fields of force. Thus, it has been possible to describe classical bag-of-enzymes biochemistry as well as membrane biochemistry in terms of transport. But it would not have been possible to explain biological transport in terms of classical transformational biochemistry or chemistry. The recognition of this conceptual asymmetry in favour of transport has seemed to be upsetting to some biochemists and chemists; and they have resisted the shift towards thinking primarily in terms of the vectorial forces and co-linear displacements of ligands in place of their much less informative scalar products that correspond to the conventional scalar energies. Nevertheless, considerable progress has been made in establishing vectorial metabolism and osmochemistry as acceptable biochemical disciplines embracing transport and metabolism, and bioenergetics has been fundamentally transformed as a result. 相似文献
5.
J.A. David P.J. Crowley S.G. Hall M. Battersby D.B. Sattelle 《Journal of insect physiology》1984,30(3):191-196
The actions of synthetic piperidine derivatives on the response to ionophoretically-applied acetylcholine (ACh) have been tested on the cell body membrane of the fast coxal depressor motoneurone (Ff) of the cockroach Periplaneta americana. The cis form and the cis (80%):trans (20%) mixture of 2-methyl-6-undecyl piperidine were the most effective (the half-maximal blocking action of the mixed isomers was estimated to be 6.3 × 10?5 M). Less potent was the cis (50%):trans (50%) mixture of 2-methyl-6-tridecyl piperidine. However, pure cis 2-methyl-6-tridecyl piperidine was even less effective than the mixed isomers, indicating that, in the case of the tridecyl derivative, the trans form was largely responsible for the block of the ACh response.Cis 2-Methyl-6-undecyl piperidine failed to inhibit the binding of N-[propionyl-3H] propionylated α-bungarotoxin to metathoracic ganglion homogenates at concentrations up to 1.0 × 10?4 M. Also, block of ACh-induced current by 2-methyl-6-undecyl piperidine (cis 80%:trans 20%) was largely independent of membrane potential in the range ?120 mV to ?60 mV, indicating an interaction with the closed ACh receptor/ion channel complex at a site which, in the case of the cis isomer, is separate from the binding site for α-bungarotoxin. 相似文献
6.
Prediction of thermodynamic parameters of protein-protein and antigen-antibody complex formation from high resolution structural parameters has recently received much attention, since an understanding of the contributions of different fundamental processes like hydrophobic interactions, hydrogen bonding, salt bridge formation, solvent reorganization etc. to the overall thermodynamic parameters and their relations with the structural parameters would lead to rational drug design. Using the results of the dissolution of hydrocarbons and other model compounds the changes in heat capacity (Cp), enthalpy (H) and entropy (S) have been empirically correlated with the polar and apolar surface areas buried during the process of protein folding/unfolding and protein-ligand complex formation. In this regard, the polar and apolar surfaces removed from the solvent in a protein-ligand complex have been calculated from the experimentally observed values of changes in heat capacity (Cp) and enthalpy (H) for protein-ligand complexes for which accurate thermodynamic and high resolution structural data are available, and the results have been compared with the x-ray crystallographic observations. Analyses of the available results show poor correlation between the thermodynamic and structural parameters. Probable reasons for this discrepancy are mostly related with the reorganization of water accompanying the reaction which is indeed proven by the analyses of the energetics of the binding of the wheat germ agglutinin to oligosaccharides. 相似文献
7.
Raquel Fernández-Durango José A. de Juan Horatio Zimman Francisco J. Moya Mario Garcia de la Coba Arturo Fernández-Cruz 《Journal of neurochemistry》1994,62(4):1482-1488
Abstract: Specific endothelin (ET) binding sites were characterized in membranes prepared from human cerebral cortices using binding assay and cross-linking analysis. The presence of immunoreactive (IR) ET-1 was studied by radioimmunoassay. Saturation binding experiments revealed that the K D and B max for 125 I-ET-1 and 125 l-ET-3 to membranes from gray matter were 25 ± 6 pM and 115 ± 15 fmol/mg of protein and 24 ± 5 p M and 108 ± 13 fmol/mg of protein, respectively. Similar results were obtained for white matter. In the presence of 10 n M sarafotoxin-6c, which is selective for ETB receptors, 125 I-ET-1 and 125 l-ET-3 binding was totally abolished. However, in the presence of 1 μ M BQ123, which is selective for ETA receptors, both bindings were not affected. These results suggest that the human cerebral cortex contains only ETB receptors. Cross-linking of 125 I-ET-1 and 125 l-ET-3 to membranes with disuccinimidyl suberate resulted in the labeling of two bands of 48 and 31 kDa. Concentrations of IR-ET-1 in the gray and white matter were 7.0 ± 3.2 and 2.5 ± 1.7 fmol/g wet weight, respectively. The demonstration of high-affinity ETB receptors and the presence of IRET-1 suggest that the peptide may act as a neurotransmitter or neuromodulator in the human cerebral cortex. 相似文献
8.
Graham Palmer 《Journal of bioenergetics and biomembranes》1993,25(2):145-151
Some contemporary issues relevant to the chemistry of mammalian cytochromec oxidase are discussed. These include the optical properties of heme A and the spectroscopic consequences of the differences in side-chain substitution compared to heme B; a common fallacy concerning the electrostatic exchange interaction between cytochromea
3 and CuB; the question of the number and location of the copper components of the enzyme; and the mode of binding of ligands such as cyanide and azide. 相似文献
9.
Takeshi Sagara Hiromu Egashira Mikako Okamura Ikuo Fujii Yasuyuki Shimohigashi Ken Kanematsu 《Bioorganic & medicinal chemistry》1996,4(12):2151-2166
For three-dimensional understanding of the mechanisms that control potency and selectivity of the ligand binding at the atomic level, we have analysed opioid receptor-ligand interaction based on the receptor's 3D model. As a first step, we have constructed molecular models for the multiple opioid receptor subtypes using bacteriorhodopsin as a template. The S-activated dihydromorphine derivatives should serve as powerful tools in mapping the three-dimensional structure of the μ opioid receptor, including the nature of the agonist-mediated conformational change that permits G protein-coupling to ‘second messenger’ effector molecules, and in identifying specific ligand-binding contacts with the μ opioid receptor. The analyses of the interactions of some opioid ligands with the predicted ligand binding sites are consistent with the results of the affinity labeling experiments. 相似文献
10.
Preparations by the high dilution method are reported for seven macrocyclic thioether-esters and thioether-thioesters (L1–;L7). Yields in these reactions between thiodiglycolyl dichloride and appropriate ,ω-diols or dithiols range from 10 to 51%. The compounds are characterized by 1H and 13C NMR, IR and high resolution mass spectroscopy. They react with salts of Pd(II), Pt(II) and Ag(I) to form complexes of which MX2·L2, (M = Pt, X = Cl; M = Pd, X = Cl, Br, I, SCN), [Pd(L2)2][CF3SO3]2·H2O and [Ag(L5)2][CF3SO3]·C2H5OH have been isolated and characterized by elemental analysis, IR and NMR spectroscopy. NMR spectra indicate reversible dissociation of the ligand occurs in dimethyl sulfoxide solvent for PdCl2·L2 but not for the Pt analogue. For PtCl2·L2, spectra indicate that the ligand is undergoing a conformational ‘wag’ about its pair of equivalent sulfurs. These remain bound to the metal while the unique sulfur moves from the apical position of the coordination sphere to a non-coordinated situation. Simultaneously, inversions at the bound sulfurs are occurring. 相似文献