全文获取类型
收费全文 | 494篇 |
免费 | 41篇 |
国内免费 | 51篇 |
专业分类
化学 | 543篇 |
晶体学 | 1篇 |
综合类 | 11篇 |
数学 | 4篇 |
物理学 | 27篇 |
出版年
2024年 | 2篇 |
2023年 | 14篇 |
2022年 | 43篇 |
2021年 | 55篇 |
2020年 | 32篇 |
2019年 | 17篇 |
2018年 | 18篇 |
2017年 | 11篇 |
2016年 | 22篇 |
2015年 | 23篇 |
2014年 | 36篇 |
2013年 | 37篇 |
2012年 | 35篇 |
2011年 | 22篇 |
2010年 | 26篇 |
2009年 | 25篇 |
2008年 | 29篇 |
2007年 | 21篇 |
2006年 | 19篇 |
2005年 | 15篇 |
2004年 | 15篇 |
2003年 | 12篇 |
2002年 | 8篇 |
2001年 | 4篇 |
2000年 | 7篇 |
1999年 | 4篇 |
1998年 | 7篇 |
1997年 | 6篇 |
1996年 | 3篇 |
1995年 | 3篇 |
1994年 | 3篇 |
1993年 | 2篇 |
1992年 | 1篇 |
1991年 | 1篇 |
1988年 | 2篇 |
1987年 | 1篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1981年 | 1篇 |
1980年 | 1篇 |
1976年 | 1篇 |
排序方式: 共有586条查询结果,搜索用时 15 毫秒
1.
A three-dimensional pharmacophore model was developed from a series of inhibitors of Aurora A kinase to discover new potent anti-cancer agents using the HypoGen module in the Catalyst software. The pharmacophore model was developed based on the structure of 20 currently available inhibitors, which were carefully selected from the literature. The best hypothesis (Hypo 1) was defined by four features: one hydrogen-bond donor and three hy- drophobic points, with the best correlation coefficient of 0.909, the lowest rms deviation of 1.563, and the highest cost difference of 99.075. The Hypo 1 was then validated by a test set consisting of 24 compounds and by a cross-validation of 95% confidence level through randomizing the data using the CatScramble program, which suggested that a predictive pharmacophore model had been successfully obtained. 相似文献
2.
An amperometric sensor for the detection of ethanol has been designed. The sensing layer consists of alcohol dehydrogenase (ADH), NADH oxidase and NAD+-dextran, entrapped together in a matrix of poly(vinyl alcohol) bearing styrylpyridinium groups (PVA-SbQ). Measurements have been carried out at a low oxidizing potential (equivalent to 250 mV vs. SCE) to detect hexacyanoferrate(II), thus avoiding interferences due to presence of oxidizable compounds in real samples. The influence of the amount of polymer, enzymes and coenzyme in the sensing layer on the sensor sensitivity, linear range and operational stability has been studied. The sensitivity was close to 2 mA 1 mol−1, with a linear range 3 × 10−7 −2 × 10−4M and a response time <2 min. Good operational stability was observed, allowing more than 40 reproducible assays without NAD+ addition. Alcoholic beverages were analysed with the use of sensor and the results showed good correlation with those obtained using a standard spectrophotometric procedure. 相似文献
3.
Broussy S Coppel Y Nguyen M Bernadou J Meunier B 《Chemistry (Weinheim an der Bergstrasse, Germany)》2003,9(9):2034-2038
Isoniazid (INH) is easily oxidized with manganese(III) pyrophosphate, a chemical model of the KatG protein involved in activation of INH inside the bacteria Mycobacterium tuberculosis. Performed in the presence of NAD(+), this oxidation generates a family of isomeric INH-NAD(H) adducts, which have been shown to be effective inhibitors of InhA, an enzyme essential in mycolic acid biosynthesis. In this work, we fully characterized by (1)H and (13)C NMR spectroscopy four main species of INH-NAD(H) adducts that coexist in solution. Two of them are open diastereoisomers consisting of the covalent attachment of the isonicotinoyl radical at position four of the nicotinamide coenzyme. The other two result from a cyclization involving the amide group from the nicotinamide and the carbonyl group from the isonicotinoyl radical to give diastereoisomeric hemiamidals. Although an INH-NAD(H) adduct with a 4S configuration has been characterized within the active site of InhA from Xray crystallography and this bound adduct interpreted as an open form (Rozwarski et al., Science 1998, 279, 98-102), it is legitimate to raise the question about the effective active form(s), open or cyclic, of INH-NAD(H) adduct(s). Is there a single active form or are several forms able to inhibit the InhA activity with different levels of inhibitory potency? 相似文献
4.
《Electroanalysis》2004,16(12):1051-1058
The voltammetric behavior of α‐ketoglutarate (α‐KG) at the hanging mercury drop electrode (HMDE) has been investigated in acetate buffer solution. Under the optimum experimental conditions (pH 4.5, 0.2 M NaAc‐HAc buffer solution), a sensitive reductive wave of α‐KG was obtained by linear scan voltammetry (LSV) and the peak potential was ?1.18 V (vs. SCE), which was an irreversible adsorption wave. The kinetic parameters of the electrode process were α=0.3 and ks=0.72 1/s. There was a linear relationship between peak current ip, α‐KG and α‐KG concentration in the range of 2×10?6–8×10?4 M α‐KG. The detection limit was 8×10?7 M and the relative standard deviation was 2.0% (Cα‐KG=8×10?4 M, n=10). Applications of the reductive wave of α‐KG for practical analysis were addressed as follows: (1) It can be used for the quantitative analysis of α‐KG in biological samples and the results agree well with those obtained from the established ultraviolet spectrophotometric method. (2) Utilizing the complexing effect between α‐KG and aluminum, a linear relationship holds between the decrease of peak current of α‐KG Δip and the added Al concentration Cequation/tex2gif-inf-5.gif in the range of 5.0×10?6–2.5×10?4 M. The detection limit was 2.2×10?6 M and the relative standard deviation was 3.1% (Cequation/tex2gif-inf-6.gif=4×10?5 M, n=10). It was successfully applied to the detection of aluminum in water and synthetic biological samples with satisfactory results, which were consistent with those of ICP‐AES. (3) It was also applied to study the effect of AlIII on the glutamate dehydrogenase (GDH) activity in the catalytically reaction of α‐KG+NH +NADH?L ‐glutamate+NAD++H2O by differential pulse polarography (DPP) technique. By monitoring DPP reductive currents of NAD+ and α‐KG, an elementary important result was found that Al could greatly affect the activity of GDH. This study could be attributed to intrinsic understanding of the aluminum's toxicity in enzyme reaction processes. 相似文献
5.
Chao Zhang 《Tetrahedron》2007,63(26):5832-5838
The ability to inhibit any protein kinase of interest with a small molecule is enabled by a combination of genetics and chemistry. Genetics is used to modify the active site of a single kinase to render it distinct from all naturally occurring kinases. Next, organic synthesis is used to develop a small molecule, which does not bind to wild-type kinases but is a potent inhibitor of the engineered kinase. This approach, termed chemical genetics, has been used to generate highly potent mutant kinase-specific inhibitors based on a pyrazolopyrimidine scaffold. Here, we asked if the selectivity of the resulting pyrazolopyrimidines could be improved, as they inhibit several wild-type kinases with low-micromolar IC50 values. Our approach to improve the selectivity of allele-specific inhibitors was to explore a second kinase inhibitor scaffold. A series of 6,9-disubstituted purines was designed, synthesized, and evaluated for inhibitory activity against several kinases in vitro and in vivo. Several purines proved to be potent inhibitors against the analog-sensitive kinases and exhibited greater selectivity than the existing pyrazolopyrimidines. 相似文献
6.
7.
Summary We have carried out up to 8.0 ns molecular dynamics simulation on the ATP-bound complexes of EGFR and HER-2 (homology model)
receptor kinase domains to explore the possible consequences of amino acid residue changes in or close to the ATP site that
might provide insights for selectivity of these kinases towards ATP site inhibitors. The simulation results show the formation
of a channel under Thr766 following the movement of the side chain of Gln767 away from the hinge in EGFR. In HER-2, a similar
movement of Gln799 occurs, but a simultaneous movement of Arg784 towards the hinge region occurs that tends to close the channel.
The movement of Arg784 in HER-2 appears to result from the absence of an anchoring residue like Asp746 in EGFR, which has
been changed to Gly778 in HER-2. In EGFR, this Arg784 is held away from the hinge region by interaction with Asp746, thereby
leaving the channel open. This might be an important contributory factor to differences in selectivity of the ligands between
the two kinases, probably more so than the conservative change of Cys751 of EGFR to serine in HER-2 at the ATP site. 相似文献
8.
辅酶NAD(P)H在生物体内起着重要的调节作用, 已引起了有机化学工作者极大的兴趣, 尤其是在还原反应的立体选择性上, 人们已经开展了大量的研究工作. 讨论了NAD(P)H模型分子进行立体专一性还原反应的影响因素, 并对NAD(P)H模型分子的研究工作做了总结. 相似文献
9.
A facile approach to chiral dihydroquinazolinone derivatives has been described via biomimetic asymmetric reduction of quinazolinones with chiral and regenerable NAD(P)H models. The utility of this method was demonstrated by a concise synthesis of the bromodomain protein divalent inhibitor. 相似文献
10.
New conformationally restricted analogues of tumor promoter (−)-indolactam-V (1), indolinelactam-Vs (8, 11) and their hexyl derivatives at position 1 or 7 (9, 10, 12, 13), were synthesized from 1. (3R)-Indolinelactam-V (8) adopted a conformation similar to the twist form of 1 with a cis amide, while the conformation of (3S)-indolinelactam-V (11) was close to that of the sofa form of 1 with a trans amide. 7-Hexyl derivatives of 8 and 11 (10, 13) showed binding affinities for C1 domains of protein kinase C (PKC) isozymes compared to 1, but exhibited little selectivity among these PKC isozymes. However, introduction of the hexyl group at position 1 of 8 and 11 significantly enhanced their binding selectivity for novel PKC isozymes. The best selectivity for novel PKC isozymes was observed in (3S)-1-hexylindolinelactam-V (12) with a sofa-like conformation. These results suggest that a sofa-restricted analogue of 1 with a hydrophobic chain at an appropriate position would be a promising lead for designing agents with a high selectivity for novel PKC isozymes. 相似文献