全文获取类型
收费全文 | 4992篇 |
免费 | 731篇 |
国内免费 | 441篇 |
专业分类
化学 | 4826篇 |
晶体学 | 15篇 |
力学 | 27篇 |
综合类 | 22篇 |
数学 | 32篇 |
物理学 | 269篇 |
综合类 | 973篇 |
出版年
2024年 | 13篇 |
2023年 | 99篇 |
2022年 | 263篇 |
2021年 | 375篇 |
2020年 | 353篇 |
2019年 | 221篇 |
2018年 | 203篇 |
2017年 | 230篇 |
2016年 | 336篇 |
2015年 | 304篇 |
2014年 | 355篇 |
2013年 | 408篇 |
2012年 | 341篇 |
2011年 | 320篇 |
2010年 | 256篇 |
2009年 | 284篇 |
2008年 | 245篇 |
2007年 | 245篇 |
2006年 | 224篇 |
2005年 | 181篇 |
2004年 | 172篇 |
2003年 | 145篇 |
2002年 | 89篇 |
2001年 | 68篇 |
2000年 | 65篇 |
1999年 | 81篇 |
1998年 | 45篇 |
1997年 | 48篇 |
1996年 | 38篇 |
1995年 | 31篇 |
1994年 | 23篇 |
1993年 | 17篇 |
1992年 | 14篇 |
1991年 | 17篇 |
1990年 | 12篇 |
1989年 | 10篇 |
1988年 | 8篇 |
1987年 | 1篇 |
1986年 | 4篇 |
1985年 | 2篇 |
1984年 | 3篇 |
1983年 | 1篇 |
1982年 | 2篇 |
1981年 | 6篇 |
1980年 | 2篇 |
1979年 | 3篇 |
1971年 | 1篇 |
排序方式: 共有6164条查询结果,搜索用时 15 毫秒
91.
喜树碱类抗肿瘤药物作用模式的柔性分子对接研究 总被引:3,自引:0,他引:3
研究采用柔性分子对接技术,将15个喜树碱类化合物对接到拓扑异构酶I (Topo I)-DNA切割复合物中,从原子水平和分子力场角度阐明了喜树碱类抗肿瘤药 物与DNA,Topo I的相互作用机制。研究发现,喜树碱分子插入Topp I-DNA复合物 的切割位点,并与Asn722,Asp533,Lys532和Lys720形成氢键作用网络。定量构效 关系研究进一步表明喜树碱分子可以与Topo I-DNA切割复合物形成电荷迁移作用。 该对接模型系统解释了喜树碱类化合物的构效关系、定点突变等诸多实验事实,为 下一步设计、合成新型高效的喜树碱类衍生物打下了坚实基础。 相似文献
92.
93.
Kenjiro Hattori Akira Kenmoku Tsukasa Mizuguchi Daisuke Ikeda Mamoru Mizuno Toshiyuki Inazu 《Journal of inclusion phenomena and macrocyclic chemistry》2006,56(1-2):9-16
A synthetic series of heptakis-galactose-branched cyclodextrins (termed CDs) having a longer spacer arm using two amino-caproic acids as an enlarging unit were prepared. Starting with heptakis-amino-β-CD or heptakis-amino-caproic-amide-β-CD, treated with galactosyl-glucono-amide-caproic acid, the new compounds heptakis (Gal-cap1)-CD (4) or heptakis (Gal-cap2)-CD (5) were obtained. The longer galactose spacer arm extremely favors the PNA association. The effect of branch length on K with PNA was enhanced up to 138-fold 3 as well as with DXR enhanced up to 81-fold. Hexakis (Gal-cap2)-CD (6) was prepared and the association constants with rat liver cells were observed to be 2.5 × 1010 M−1. A multi-high mannose type oligosaccharide branched CD (7) showed a large association constant with DXR up to 1.1 × 109 M−1. The two-dimensional map for the association constants of newly synthesized oligosaccharide-branched CDs toward lectin or liver cells versus the association constants toward a drug (doxorubicin) suggested a method of finding a better targeting drug carrier. The structural effect of the oligosaccharide-CDs showed that the number and length of the branch were dominant factors in designing for enhanced dual recognition. 相似文献
94.
Y. Sun T.J.A. Ewing A.G. Skillman I.D. Kuntz 《Journal of computer-aided molecular design》1998,12(6):597-604
We have developed a strategy for efficiently docking a large combinatorial library into a target receptor. For each scaffold orientation, all potential fragments are attached to the scaffold, their interactions with the receptor are individually scored and factorial combinations of fragments are constructed. To test its effectiveness, this approach is compared to two simple control algorithms. Our method is more efficient than the controls at selecting best scoring molecules and at selecting fragments for the construction of an exhaustive combinatorial library. We also carried out a retrospective analysis of the experimental results of a 10×10×10 exhaustive combinatorial library. An enrichment factor of approximately 4 was found for identifying the compounds in the library that are active at 330 nM. 相似文献
95.
Matthias Tacke Lorcan T. Allen William M. Gallagher Oscar Mendoza Franz-Josef K. Rehmann 《Journal of organometallic chemistry》2004,689(13):2242-2249
Starting from 6-(p−N,N-dimethylanilinyl)fulvene (1a) or 6-(pentamethylphenyl)fulvene (1b) [1,2-di(cyclopentadienyl)-1,2-di(p−N,N-dimethylaminophenyl)ethanediyl] titanium dichloride (2a) and [1,2-di(cyclopentadienyl)-1,2-bis(pentamethylphenyl)ethanediyl] titanium dichloride (2b) and their corresponding dithiocyanato complexes (3a, 3b) were synthesized. Titanocene 2b did not show a cytotoxic effect, but when 2a was tested against pig kidney carcinoma cells (LLC-PK) or human ovarian carcinoma cells (A2780/cp70) inhibitory concentrations (IC50) of 2.7 × 10−4 and 1.9 × 10−4 M, respectively, were observed. 相似文献
96.
Krauth-Siegel RL Bauer H Schirmer RH 《Angewandte Chemie (International ed. in English)》2005,44(5):690-715
Parasitic diseases such as sleeping sickness, Chagas' heart disease, and malaria are major health problems in poverty-stricken areas. Antiparasitic drugs that are not only active but also affordable and readily available are urgently required. One approach to finding new drugs and rediscovering old ones is based on enzyme inhibitors that paralyze antioxidant systems in the pathogens. These antioxidant ensembles are essential to the parasites as they are attacked in the human host by strong oxidants such as peroxynitrite, hypochlorite, and H2O2. The pathogen-protecting system consists of some 20 thiol and dithiol proteins, which buffer the intraparasitic redox milieu at a potential of -250 mV. In trypanosomes and leishmania the network is centered around the unique dithiol trypanothione (N1,N8-bis(glutathionyl)spermidine). In contrast, malaria parasites have a more conservative dual antioxidative system based on glutathione and thioredoxin. Inhibitors of antioxidant enzymes such as trypanothione reductase are, indeed, parasiticidal but they can also delay or prevent resistance against a number of other antiparasitic drugs. 相似文献
97.
Peptides represent an extensive class of biologically active molecules. They may be used as leads in the development of novel therapeutic agents provided the pharmacophoric information present within them can be translated into non-peptide analogs that lack the peptide backbone and are stable to proteolysis. This is the rationale for peptidomimetic drug design. Frequently, the -turn has been implicated as a conformation important for biological recognition of peptides. Empirical evidence from known peptidomimetics, coupled with a theoretical model of peptide binding and the observation that glycine and proline residues are common within the -turn, has suggested the design of molecules to mimic placement of between two and four of the side-chains. The moderate number of different -turn conformations, combined with the combinatoric nature of side-chain selection complicates the procedure. In this paper, cluster analysis has been used to classify the arrangement of C_ atoms about the various fragments of the -turn. Recombination of the observed patterns provides a general model for the -turn which may be used as an effective screen for potential peptidomimetic scaffolds in chemical databases. 相似文献
98.
Factor Xa is a serine protease which activates thrombin and plays a key regulatory role in the blood-coagulation cascade. Factor Xa is at the crossroads of the extrinsic and intrinsic pathways of coagulation and, hence, has become an important target for the design of anti-thrombotics (inhibitors). It is not known to be involved in other processes than hemostasis and its binding site is different to that of other serine proteases, thus facilitating selective inhibition. The design of high-affinity selective inhibitors of factor Xa requires knowledge of the structural and dynamical characteristics of its active site. The three-dimensional structure of factor Xa was resolved by X-ray crystallography and refined at 2.2 Å resolution by Padmanabhan and collaborators. In this article we present results from molecular dynamics simulations of the catalytic domain of factor Xa in aqueous solution. The simulations were performed to characterise the mobility and flexibility of the residues delimiting the unoccupied binding site of the enzyme, and to determine hydrogen bonding propensities (with protein and with solvent atoms) of those residues in the active site that could interact with a substrate or a potential inhibitor. The simulation data is aimed at facilitating the design of high-affinity selective inhibitors of factor Xa. 相似文献
99.
Hydroxypropyl chitosan-graft-carboxymethyl beta-cyclodextrin (HPCH-g-CM beta-CD) was synthesized by grafting CM beta-CD onto HPCH using water soluble 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as the condensing agent. Due to the presence of hydrophobic beta-CD rings onto the HPCH backbone, this polymer can be used as a matrix for controlled drug release. The adsorption of a hydrophobic model drug, ketoprofen, by HPCH-g-CM beta-CD microparticles (using tripolyphosphate as an ionic crosslinking agent) fitted well in the Langmuir isotherm equation. The drug dissolution profile showed that HPCH-g-CM beta-CD microparticles provided a slower release of the entrapped ketoprofen than chitosan, and the release behavior was influenced by the pH value of the medium. These results suggest that beta-CD grafted with chitosan derivatives may become a potential biodegradable delivery system to control the release of hydrophobic drugs with pH-responsive capability. 相似文献
100.
建立了分散固相萃取净化-超高效液相色谱-串联质谱法快速测定鱼和虾中3类(磺胺类、喹诺酮类、氯霉素类)18种抗生素及2种三苯甲烷类(孔雀石绿、隐色孔雀石绿)兽药残留。样品经磷酸氢二钾溶液水解分散,乙腈提取,提取液经氯化钠脱水、盐析后取乙腈层,经旋转蒸发仪浓缩至近干,残留物用甲醇定容至1.0 mL,C18和PSA(N-丙基乙二胺)填料分散固相萃取净化,过滤膜后经ZORBAX C18色谱柱(50 mm×2.1 mm,1.8 μm)分离,正、负离子多反应监测模式采集数据,同位素内标法定量。实验结果表明,20种兽药在0.2~300 μg/L范围内具有良好的线性关系,检出限为0.1~0.6 μg/kg,定量限为0.3~1.8 μg/kg,相关系数均大于0.99。在1、5和20倍定量限加标浓度水平下,平均回收率为72.5%~118%,相对标准偏差(RSD)为1.9%~9.8%。该方法具有前处理简单、检测效率高、成本低等优点,适用于鱼和虾中多类兽药残留的同时测定。 相似文献