全文获取类型
收费全文 | 222篇 |
免费 | 20篇 |
国内免费 | 1篇 |
出版年
2022年 | 2篇 |
2021年 | 5篇 |
2020年 | 2篇 |
2019年 | 4篇 |
2018年 | 5篇 |
2017年 | 7篇 |
2016年 | 11篇 |
2015年 | 10篇 |
2014年 | 14篇 |
2013年 | 14篇 |
2012年 | 11篇 |
2011年 | 19篇 |
2010年 | 5篇 |
2009年 | 7篇 |
2008年 | 8篇 |
2007年 | 19篇 |
2006年 | 3篇 |
2005年 | 2篇 |
2004年 | 4篇 |
2003年 | 4篇 |
2002年 | 5篇 |
2001年 | 8篇 |
2000年 | 6篇 |
1999年 | 5篇 |
1998年 | 2篇 |
1997年 | 2篇 |
1996年 | 5篇 |
1994年 | 3篇 |
1992年 | 6篇 |
1990年 | 3篇 |
1989年 | 1篇 |
1988年 | 3篇 |
1987年 | 1篇 |
1986年 | 2篇 |
1985年 | 1篇 |
1983年 | 1篇 |
1982年 | 3篇 |
1979年 | 3篇 |
1977年 | 2篇 |
1976年 | 2篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1973年 | 2篇 |
1972年 | 1篇 |
1971年 | 3篇 |
1970年 | 3篇 |
1969年 | 3篇 |
1968年 | 1篇 |
1967年 | 2篇 |
1965年 | 1篇 |
排序方式: 共有243条查询结果,搜索用时 15 毫秒
61.
Marine derivatives are of great pharmaceutical interest as inhibitory compound and search of bioactive compounds from Marine
organism which is relatively new to medicinal chemistry. Our main aim in the study is to screen possible inhibitors against
CCR5 which acts as co-receptor M-tropic HIV-1, through virtual screening of 122 Marine derived compounds from various
organisms known to have biological activity. Homology Model of CCR5 was constructed using MODELLER and the Model was energy
minimized and validated using PROCHECK to obtain a stable structure, which was further used for virtual screening of Marine
derived compounds through molecular Docking studies using GOLD. The Docked complexes were validated and Enumerated based on
the GOLD Scoring function to pick out the best Marine inhibitor based on GOLD score. Thus from the entire 122 Marine
compounds which were Docked, we got best 4 of them with optimal GOLD Score.
(LAMIVUDINE: 45.0218, BATZELLINE-D: 44.3852.ACYCLOVIR: 43.1362 and THIIOACETAMIDE: 42.7412) Further the Complexes were analyzed
through LIGPLOT for their interaction for the 4 best docked Marine compounds. Thus from the Complex scoring and binding ability its
deciphered that these Marine compounds could be promising inhibitors for M-tropic HIV-1 using CCR5 as Drug target yet pharmacological
studies have to confirm it. 相似文献
62.
Variations among cell lines in the synthesis of sphingolipids in de novo and recycling pathways 总被引:1,自引:0,他引:1
There are several pathways for the incorporation of sugars into
glycosphingolipids (GSL). Sugars can be added to ceramide that contains
sphinganine (dihydrosphingosine) synthesized de novo (pathway 1), to
ceramide synthesized from sphingoid bases produced by hydrolysis of
sphingolipids (pathway 2), and into GSL recycling from the endosomal
pathway through the Golgi (pathway 3). We reported previously the
surprising observation that SW13 cells, a human adrenal carcinoma cell
line, synthesize most of their GSL in pathway 2. We now present data on the
synthesis of GSL in four additional cell lines. Approximately 90% of sugar
incorporation took place in pathway 2, and 10% or less in pathway 1, in
human foreskin fibroblasts and NB41A3 neuroblastoma cells. In contrast,
approximately 50-90% of sugar incorporation took place in pathway 1 in
C2C12 myoblasts. The C2C12 cells divide more rapidly and synthesize 10-14
times as much GSL as the other three cell lines. In C6 glioma cells,
approximately 30% of sugar incorporation occurred in pathway 1 and 60% in
pathway 2. There was no relation between the utilization of pathways for
GSL and sphingomyelin synthesis in foreskin fibroblasts and C2C12 cells. In
both cells pathways 1 and 2 each accounted for 50% of incorporation of
choline into sphingomyelin. In five of the six cell lines that we have
studied, most GSL synthesis takes place in pathway 2. We suggest that when
the need for synthesis is relatively low, as in slowly dividing cells, GSL
are synthesized predominantly from sphingoid bases salvaged from the
hydrolytic pathway. When cells are dividing more rapidly, the need for
increased synthesis is met by upregulating the de novo pathway.
相似文献
63.
Lemke CT Titolo S von Schwedler U Goudreau N Mercier JF Wardrop E Faucher AM Coulombe R Banik SS Fader L Gagnon A Kawai SH Rancourt J Tremblay M Yoakim C Simoneau B Archambault J Sundquist WI Mason SW 《Journal of virology》2012,86(12):6643-6655
The emergence of resistance to existing classes of antiretroviral drugs necessitates finding new HIV-1 targets for drug discovery. The viral capsid (CA) protein represents one such potential new target. CA is sufficient to form mature HIV-1 capsids in vitro, and extensive structure-function and mutational analyses of CA have shown that the proper assembly, morphology, and stability of the mature capsid core are essential for the infectivity of HIV-1 virions. Here we describe the development of an in vitro capsid assembly assay based on the association of CA-NC subunits on immobilized oligonucleotides. This assay was used to screen a compound library, yielding several different families of compounds that inhibited capsid assembly. Optimization of two chemical series, termed the benzodiazepines (BD) and the benzimidazoles (BM), resulted in compounds with potent antiviral activity against wild-type and drug-resistant HIV-1. Nuclear magnetic resonance (NMR) spectroscopic and X-ray crystallographic analyses showed that both series of inhibitors bound to the N-terminal domain of CA. These inhibitors induce the formation of a pocket that overlaps with the binding site for the previously reported CAP inhibitors but is expanded significantly by these new, more potent CA inhibitors. Virus release and electron microscopic (EM) studies showed that the BD compounds prevented virion release, whereas the BM compounds inhibited the formation of the mature capsid. Passage of virus in the presence of the inhibitors selected for resistance mutations that mapped to highly conserved residues surrounding the inhibitor binding pocket, but also to the C-terminal domain of CA. The resistance mutations selected by the two series differed, consistent with differences in their interactions within the pocket, and most also impaired virus replicative capacity. Resistance mutations had two modes of action, either directly impacting inhibitor binding affinity or apparently increasing the overall stability of the viral capsid without affecting inhibitor binding. These studies demonstrate that CA is a viable antiviral target and demonstrate that inhibitors that bind within the same site on CA can have distinct binding modes and mechanisms of action. 相似文献
64.
Ramesh JL Kandimalla Willayat Yousuf Wani Binukumar BK Kiran Dip Gill 《Journal of biomedical science》2012,19(1):2
Background
One of the pathological hallmarks of Alzheimer's disease (AD) is the deposition of the ~4 kDa amyloid β protein (Aβ) within lesions known as senile plaques. Aβ is also deposited in the walls of cerebral blood vessels in many cases of AD. A substantial proportion of the Aβ that accumulates in the AD brain is deposited as Amyloid, which is highly insoluble, proteinaceous material with a β-pleated-sheet conformation and deposited extracellularly in the form of 5-10 nm wide straight fibrils. As γ-secretase catalyzes the final cleavage that releases the Aβ42 or 40 from amyloid β -protein precursor (APP), therefore, it is a potential therapeutic target for the treatment of AD. γ-Secretase cleavage is performed by a high molecular weight protein complex containing presenilins (PSs), nicastrin, Aph-1 and Pen-2. Previous studies have demonstrated that the presenilins (PS1 and PS2) are critical components of a large enzyme complex that performs γ-secretase cleavage. 相似文献65.
66.
Bacteria grown in pure culture have been the starting point for the discovery of many of the antibacterials now in use. Metagenomics, which utilizes culture-independent methods to access the collective genomes of natural bacterial populations, provides a means of exploring the antimicrobials produced by the large collections of bacteria that are known to be present in the environment but remain recalcitrant to culturing. Both novel small molecule antibiotics and new antibacterially active proteins have been identified using metagenomic approaches. The recent application of metagenomics to the discovery of bioactive small molecules, small molecule biosynthetic gene clusters and antibacterially active enzymes is discussed here. 相似文献
67.
Of the factors tested, the source and concentration of carbon and nitrogen in the medium exerted maximum effect on growth and acid production. Glucose (15%) and urea (0.14%) induced glucose oxidase synthesis and optimum yield of calcium gluconate. Potassium dihydrogen phosphate (0.2%) and magnesium sulphate (0.06%) stimulated glucose oxidase activity and calcium gluconate production. Borax at a concentration of 1.5 g/L induced maximum glucose oxidase and calcium gluconate production with increased glucose utilization. 相似文献
68.
69.
70.