全文获取类型
收费全文 | 1463篇 |
免费 | 187篇 |
国内免费 | 90篇 |
专业分类
化学 | 1689篇 |
晶体学 | 13篇 |
综合类 | 4篇 |
数学 | 4篇 |
物理学 | 30篇 |
出版年
2024年 | 2篇 |
2023年 | 18篇 |
2022年 | 35篇 |
2021年 | 116篇 |
2020年 | 100篇 |
2019年 | 71篇 |
2018年 | 50篇 |
2017年 | 57篇 |
2016年 | 73篇 |
2015年 | 77篇 |
2014年 | 82篇 |
2013年 | 146篇 |
2012年 | 86篇 |
2011年 | 70篇 |
2010年 | 67篇 |
2009年 | 91篇 |
2008年 | 81篇 |
2007年 | 71篇 |
2006年 | 79篇 |
2005年 | 78篇 |
2004年 | 73篇 |
2003年 | 69篇 |
2002年 | 26篇 |
2001年 | 15篇 |
2000年 | 16篇 |
1999年 | 14篇 |
1998年 | 11篇 |
1997年 | 6篇 |
1996年 | 10篇 |
1995年 | 15篇 |
1994年 | 14篇 |
1993年 | 5篇 |
1992年 | 6篇 |
1991年 | 3篇 |
1989年 | 3篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1981年 | 1篇 |
排序方式: 共有1740条查询结果,搜索用时 31 毫秒
21.
22.
Targeting the Two Oncogenic Functional Sites of the HPV E6 Oncoprotein with a High‐Affinity Bivalent Ligand 下载免费PDF全文
23.
Scalable Synthesis of the Potent HIV Inhibitor BMS‐986001 by Non‐Enzymatic Dynamic Kinetic Asymmetric Transformation (DYKAT) 下载免费PDF全文
Dr. Adrian Ortiz Dr. Tamas Benkovics Dr. Gregory L. Beutner Dr. Zhongping Shi Dr. Michael Bultman Dr. Jeffrey Nye Dr. Chris Sfouggatakis Dr. David R. Kronenthal 《Angewandte Chemie (International ed. in English)》2015,54(24):7185-7188
Described herein is the synthesis of BMS‐986001 by employing two novel organocatalytic transformations: 1) a highly selective pyranose to furanose ring tautomerization to access an advanced intermediate, and 2) an unprecedented small‐molecule‐mediated dynamic kinetic resolution to access a variety of enantiopure pyranones, one of which served as a versatile building block for the multigram, stereoselective, and chromatography‐free synthesis of BMS‐986001. The synthesis required five chemical transformations and resulted in a 44 % overall yield. 相似文献
24.
Philipp M. Cromm Jochen Spiegel Dr. Tom N. Grossmann Prof. Dr. Herbert Waldmann 《Angewandte Chemie (International ed. in English)》2015,54(46):13516-13537
Small GTPases are a family of GDP‐/GTP‐binding proteins that serve as biomolecular switches inside cells to control a variety of essential cellular processes. Aberrant function and regulation of small GTPases is associated with a variety of human diseases, thus rendering these proteins highly interesting targets in drug discovery. However, this class of proteins has been considered “undruggable”, as intensive decade‐long efforts did not yield clinically relevant direct modulators of small GTPases. Recently, the targeting of small GTPases has gained fresh impetus through the discovery of novel transient cavities on the protein surfaces and the application of new targeting strategies. Besides Ras proteins, other small GTPases have attracted increased attention since improved biological insight in combination with novel targeting strategies identified them as promising targets in drug discovery. This Review gives an overview of relevant aspects of the superfamily of small GTPases and summarizes recent progress and perspectives for the direct modulation of these challenging targets. 相似文献
25.
A Hot‐Segment‐Based Approach for the Design of Cross‐Amyloid Interaction Surface Mimics as Inhibitors of Amyloid Self‐Assembly 下载免费PDF全文
Dr. Erika Andreetto Dipl.‐Chem. Eleni Malideli Dr. Li‐Mei Yan Dipl.‐Ing. Michael Kracklauer MSc. Karine Farbiarz Dipl.‐Chem. Marianna Tatarek‐Nossol Prof. Dr. Gerhard Rammes M. Sc. Elke Prade Tatjana Neumüller Dr. Andrea Caporale M. Sc. Anna Spanopoulou B. Sc. Maria Bakou Prof. Dr. Bernd Reif Prof. Dr. Aphrodite Kapurniotu 《Angewandte Chemie (International ed. in English)》2015,54(44):13095-13100
The design of inhibitors of protein–protein interactions mediating amyloid self‐assembly is a major challenge mainly due to the dynamic nature of the involved structures and interfaces. Interactions of amyloidogenic polypeptides with other proteins are important modulators of self‐assembly. Here we present a hot‐segment‐linking approach to design a series of mimics of the IAPP cross‐amyloid interaction surface with Aβ (ISMs) as nanomolar inhibitors of amyloidogenesis and cytotoxicity of Aβ, IAPP, or both polypeptides. The nature of the linker determines ISM structure and inhibitory function including both potency and target selectivity. Importantly, ISMs effectively suppress both self‐ and cross‐seeded IAPP self‐assembly. Our results provide a novel class of highly potent peptide leads for targeting protein aggregation in Alzheimer’s disease, type 2 diabetes, or both diseases and a chemical approach to inhibit amyloid self‐assembly and pathogenic interactions of other proteins as well. 相似文献
26.
Dr. Lech‐Gustav Milroy Dr. Maria Bartel Dr. Morkos A. Henen Dr. Seppe Leysen Joris M. C. Adriaans Prof. Dr. Luc Brunsveld Dr. Isabelle Landrieu Dr. Christian Ottmann 《Angewandte Chemie (International ed. in English)》2015,54(52):15720-15724
The discovery of novel protein–protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein–stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine X‐ray crystallographic data from both stabilizer and inhibitor co‐crystal complexes of the adapter protein 14‐3‐3 to characterize, down to the atomic scale, inhibitors of the 14‐3‐3/Tau PPI, a potential drug target to treat Alzheimer’s disease. The most potent compound notably inhibited the binding of phosphorylated full‐length Tau to 14‐3‐3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer–protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14‐3‐3 and other PPIs. 相似文献
27.
In this work, the performance of nine ionic liquids (ILs) as thermodynamic hydrate inhibitors is investigated. The dissociation temperature is determined for methane gas hydrates using a high pressure micro deferential scanning calorimeter between (3.6 and 11.2) MPa. All the aqueous IL solutions are studied at a mass fraction of 0.10. The performance of the two best ILs is further investigated at various concentrations. Electrical conductivity and pH of these aqueous IL solutions (0.10 mass fraction) are also measured. The enthalpy of gas hydrate dissociation is calculated by the Clausius–Clapeyron equation. It is found that the ILs shift the methane hydrate (liquid + vapour) equilibrium curve (HLVE) to lower temperature and higher pressure. Our results indicate 1-(2-hydroxyethyl) 3-methylimidazolium chloride is the best among the ILs studied as a thermodynamic hydrate inhibitor. A statistical analysis reveals there is a moderate correlation between electrical conductivity and the efficiency of the IL as a gas hydrate inhibitor. The average enthalpies of methane hydrate dissociation in the presence of these ILs are found to be in the range of (57.0 to 59.1) kJ ⋅ mol−1. There is no significant difference between the dissociation enthalpy of methane hydrate either in the presence or in absence of ILs. 相似文献
28.
QM/MM modeling of the hydroxylation of the androstenedione substrate catalyzed by cytochrome P450 aromatase (CYP19A1) 下载免费PDF全文
Ignacio Viciano Raquel Castillo Sergio Martí 《Journal of computational chemistry》2015,36(23):1736-1747
CYP19A1 aromatase is a member of the Cytochrome P450 family of hemeproteins, and is the enzyme responsible for the final step of the androgens conversion into the corresponding estrogens, via a three‐step oxidative process. For this reason, the inhibition of this enzyme plays an important role in the treatment of hormone‐dependent breast cancer. The first catalytic subcycle, corresponding to the hydroxilation of androstenedione, has been proposed to occur through a first hydrogen abstraction and a subsequent oxygen rebound step. In present work, we have studied the mechanism of the first catalytic subcycle by means of hybrid quantum mechanics/molecular mechanics methods. The inclusion of the protein flexibility has been achieved by means of Free Energy Perturbation techniques, giving rise to a free energy of activation for the hydrogen abstraction step of 13.5 kcal/mol. The subsequent oxygen rebound step, characterized by a small free energy barrier (1.5 kcal/mol), leads to the hydroxylated products through a highly exergonic reaction. In addition, an analysis of the primary deuterium kinetic isotopic effects, calculated for the hydrogen abstraction step, reveals values (~10) overpassing the semiclassical limit for the C? H, indicating the presence of a substantial tunnel effect. Finally, a decomposition analysis of the interaction energy for the substrate and cofactor in the active site is also discussed. According to our results, the role of the enzymatic environment consists of a transition state stabilization by means of dispersive and polarization effects. © 2015 Wiley Periodicals, Inc. 相似文献
29.
Development of a method to screen and isolate potential α‐glucosidase inhibitors from Panax japonicus C.A. Meyer by ultrafiltration,liquid chromatography,and counter‐current chromatography 下载免费PDF全文
A new assay based on ultrafiltration, liquid chromatography and mass spectrometry was developed for the rapid screening and identification of the ligands for α‐glucosidase from the extract of Panax japonicus. Six saponins were identified as α‐glucosidase inhibitors. Subsequently, the specific binding ligands, namely, notoginsenoside R1, ginsenoside Rb1, chikusetsusaponin V, chikusetsusaponin IV, chikusetsusaponin IVa, and ginsenoside Rd (the purities were 94.18, 95.43, 96.09, 93.26, 94.50, 93.86%, respectively) were separated by counter‐current chromatography using two‐phase solvent systems composed of tert‐butyl methyl ether, acetonitrile, 0.1% aqueous formic acid (3.8:1.0:4.4, v/v/v) and the solvent system composed of methylene chloride, isopropanol, methanol, 0.1% aqueous formic acid (5.8:1.0:6.0:2.2, v/v/v). The results demonstrate that ultrafiltration, liquid chromatography and mass spectrometry combined with high‐speed counter‐current chromatography might provide not only a powerful tool for screening and isolating α‐glucosidase inhibitors in complex samples but also a useful platform for discovering bioactive compounds for the prevention and treatment of diabetes mellitus. 相似文献
30.
De Novo Design and Synthesis of a γ‐Turn Peptidomimetic Scaffold and Its Application as JNK3 Allosteric Ligand 下载免费PDF全文
As a way to develop a neuroprotective agent for the JNK3‐JIP1‐binding site, peptidomimetics of JIP‐1 as JNK3 allosteric regulators have been examined. The study consisted of in silico scaffold hopping, molecular docking, solution and solid‐phase peptide syntheses, and Kd measurements using surface plasmon resonance. As a peptidomimetic of JIP1, heptamer mimetic 16 (Kd=2.72 μm ) displayed a higher affinity than decamer JIP1 (Kd=23.6 μm ). The high affinity of 16 implies that the characteristic γ‐turn mimetic structure, “”Φ‐X‐Φ“ hydrophobic motif in 16 , increased its affinity toward the JIP‐site of JNK3. 相似文献