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排序方式: 共有474条查询结果,搜索用时 31 毫秒
81.
Based on the structure of Go6976, a known isoform‐selective protein kinase C inhibitor, a benzofuran analogue (1) was designed. This analogue was synthesized by coupling of benzofuran 3‐acetic acid and 8‐oxo‐tryptamine and subsequent intramolecular Dieckmann condensation, alkylation, oxidative photocydization and cyanation reaction of mesylate. 相似文献
82.
Xinyi Li Zengxin Qi Duan Ni Shaoyong Lu Liang Chen Xiangyu Chen 《Molecules (Basel, Switzerland)》2021,26(18)
Mutations in leucine-rich repeat kinase 2 (LRRK2) are recognized as the most frequent cause of Parkinson’s disease (PD). As a multidomain ROCO protein, LRRK2 is characterized by the presence of both a Ras-of-complex (ROC) GTPase domain and a kinase domain connected through the C-terminal of an ROC domain (COR). The bienzymatic ROC–COR–kinase catalytic triad indicated the potential role of GTPase domain in regulating kinase activity. However, as a functional GTPase, the detailed intrinsic regulation of the ROC activation cycle remains poorly understood. Here, combining extensive molecular dynamics simulations and Markov state models, we disclosed the dynamic structural rearrangement of ROC’s homodimer during nucleotide turnover. Our study revealed the coupling between dimerization extent and nucleotide-binding state, indicating a nucleotide-dependent dimerization-based activation scheme adopted by ROC GTPase. Furthermore, inspired by the well-known R1441C/G/H PD-relevant mutations within the ROC domain, we illuminated the potential allosteric molecular mechanism for its pathogenetic effects through enabling faster interconversion between inactive and active states, thus trapping ROC in a prolonged activated state, while the implicated allostery could provide further guidance for identification of regulatory allosteric pockets on the ROC complex. Our investigations illuminated the thermodynamics and kinetics of ROC homodimer during nucleotide-dependent activation for the first time and provided guidance for further exploiting ROC as therapeutic targets for controlling LRRK2 functionality in PD treatment. 相似文献
83.
Serhii A. Liakhov Igor A. Schepetkin Olexander S. Karpenko Hanna I. Duma Nadiia M. Haidarzhy Liliya N. Kirpotina Anastasia R. Kovrizhina Andrei I. Khlebnikov Irina Y. Bagryanskaya Mark T. Quinn 《Molecules (Basel, Switzerland)》2021,26(18)
c-Jun N-terminal kinase (JNK) plays a central role in stress signaling pathways implicated in important pathological processes, including rheumatoid arthritis and ischemia-reperfusion injury. Therefore, inhibition of JNK is of interest for molecular targeted therapy to treat various diseases. We synthesized 13 derivatives of our reported JNK inhibitor 11H-indeno[1,2-b]quinoxalin-11-one oxime and evaluated their binding to the three JNK isoforms and their biological effects. Eight compounds exhibited submicromolar binding affinity for at least one JNK isoform. Most of these compounds also inhibited lipopolysaccharide (LPS)-induced nuclear factor-κB/activating protein 1 (NF-κB/AP-1) activation and interleukin-6 (IL-6) production in human monocytic THP1-Blue cells and human MonoMac-6 cells, respectively. Selected compounds (4f and 4m) also inhibited LPS-induced c-Jun phosphorylation in MonoMac-6 cells, directly confirming JNK inhibition. We conclude that indenoquinoxaline-based oximes can serve as specific small-molecule modulators for mechanistic studies of JNKs, as well as potential leads for the development of anti-inflammatory drugs. 相似文献
84.
85.
Peter Stanetty Jürgen Röhrling Michael Schnürch Marko D. Mihovilovic 《Tetrahedron》2006,62(10):2380-2387
Analogs of 3-{4-[2-(3-chlorophenylamino)-pyrimidin-4-yl]-pyridin-2-yl-amino}-propanol (CGP 60474) were synthesized as useful models for the evaluation of structure-activity relationships of phenylamino-pyrimidine-type protein kinase C inhibitors. The approach involved Pd-assisted cross-coupling as the key step. Negishi-type coupling was performed both with free amino functionalities and Boc-protected amines present and showed that the protection-cross-coupling-deprotection sequence leads to significantly higher yields. 相似文献
86.
《Journal of computational chemistry》2018,39(19):1307-1318
Drug‐binding kinetics could play important roles in determining the efficacy of drugs and has caught the attention of more drug designers. Using the dissociation of 1H‐pyrrolo[2,3‐b]‐pyridines from the focal adhesion kinase as an example, this work finds that steered molecular dynamics simulations could help screen compounds with long‐residence times. It also reveals a two‐step mechanism of ligand dissociation resembling the release of ADP from protein kinase A reported earlier. A phenyl group attaching to the pyrrole prolongs residence time by creating a large activation barrier for transition from the bound to the intermediate state when it becomes exposed to the solvent. Principal component analysis shows that ligand dissociation does not couple with large‐scale collective motions of the protein involving many of its amino acids. Rather, a small subset of amino acids dominates. Some of these amino acids do not contact the ligands directly along the dissociation pathways and could exert long‐range allosteric effects. © 2018 Wiley Periodicals, Inc. 相似文献
87.
Calmodulin-dependent protein kinase (CAMK) is physiologically activated in fertilized human oocytes and is involved in the Ca2+ response pathways that link the fertilization calmodulin signal to meiosis resumption and cortical granule exocytosis. The kinase has an unstructured C-terminal tail that can be recognized and bound by the PDZ5 domain of its cognate partner, the multi-PDZ domain protein (MUP). In the current study, we reported a rational biomolecular design of halogen-bonding system at the complex interface of CAMK’s C-terminal peptide with MUP PDZ5 domain by using high-level computational approaches. Four organic halogens were employed as atom probes to explore the structural geometry and energetic property of designed halogen bonds in the PDZ5–peptide complex. It was found that the heavier halogen elements such as bromine Br and iodine I can confer stronger halogen bond but would cause bad atomic contacts and overlaps at the complex interface, while fluorine F cannot form effective halogen bond in the complex. In addition, the halogen substitution at different positions of peptide’s aromatic ring would result in distinct effects on the halogen-bonding system. The computational findings were then verified by using fluorescence analysis; it is indicated that the halogen type and substitution position play critical role in the interaction strength of halogen bonds, and thus the PDZ5–peptide binding affinity can be improved considerably by optimizing their combination. 相似文献
88.
Kashif Maqbool Khan Lutfun Nahar Abdul Mannan Ihsan Ul-Haq Muhammad Arfan Ghazanfar Ali Khan 《Natural product research》2018,32(18):2193-2201
Trillium govanianum Wall. ex D. Don (Melanthiaceae alt. Trilliaceae), commonly known as ‘nagchhatry’ or ‘teen patra’, distributed from Pakistan to Bhutan about 2500–3800 m altitude is indigenous to Himalayas region. In folk medicine the plant has been reported for the treatment of wound healing, sepsis and in various sexual disorders. This paper reports, for the first time, to evaluate the cytotoxicity, in vitro anti-leishmanial (promastigotes) and fingerprint HPLC-photodiode array analysis of the MeOH extract of the roots of T. govanianum and its solid phase extraction fractions. Reverse phase HPLC-PDA based quantification revealed the presence of significant amount of quercetin, myrecetin and kaemferol ranging from 0.221to 0.528 μg/mg DW. MeOH extract revealed distinguishable protein kinase inhibitory activity against Streptomyces 85E strain with 18 mm bald phenotype. The remarkable toxicity profile against brine shrimps and leishmanial was manifested by MeOH extract with LC50 10 and 38.5 μg/mL, respectively. 相似文献
89.
90.
Indirubin, present in extracts of Isatis tinctoria and some other plant species, has promising cytotoxicity against a variety of cell lines by inhibition of cyclin‐dependent kinases. Chemical synthesis of its derivatives relies on the combination of isatins and 2,3‐dihydro‐1H‐indol‐3‐one (‘indoxyl’) derivatives and usually yields indigo as well as other by‐products. Inspection of the hydrolysis of the long‐known condensation products of 2‐thioxothiazolidin‐4‐one with isatins gave useful hints for an improved synthesis of indirubins: this reaction does not yield quinoline derivatives but 2‐(2,3‐dihydro‐2‐oxo‐1H‐indol‐3‐ylidene)‐2‐sulfanyl acetic acids. By substitution of the sulfanyl group in this oxindoles with anilines and straightforward cyclization under Nazarov conditions, a broad variety of indirubins substituted in the indoxyl ring system are thus available, usually in very good purity and yield. Use of naphthylamines in this reaction sequence yields various fluorescent substances with λfl at ca. 630 nm. 相似文献