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101.
Microtubules are tube-shaped, filamentous and cytoskeletal proteins that are essential in all eukaryotic cells. Microtubule is an attractive and promising target for anticancer agents. In this study, three-dimensional quantitative structure activity relationships (3D-QSAR) including comparative molecular field analysis, CoMFA, and comparative molecular similarity indices analysis, CoMSIA, were performed on a set of 45 (E)-N-Aryl-2-ethene-sulfonamide analogues as microtubule-targeted anti-prostate cancer agents. Automated grid potential analysis, AutoGPA module in Molecular Operating Environment 2009.10 (MOE) as a new 3D-QSAR approach with the pharmacophore-based alignment was carried out on the same dataset. AutoGPA-based 3D-QSAR model yielded better prediction parameters than CoMFA and CoMSIA. Based on the contour maps generated from the models, some key features were identified in (E)-N-Aryl-2-arylethene-sulfonamide analogues that were responsible for the anti-cancer activity. Virtual screening was performed based on pharmacophore modeling and molecular docking to identify the new inhibitors from ZINC database. Seven top ranked compounds were found based on Gold score fitness function. In silico ADMET studies were performed on compounds retrieved from virtual screening in compliance with the standard ranges. 相似文献
102.
This article broadens the scheme previously developed to associate topology optimization with additive manufacturing through the use of a virtual skeleton, consisting in solving the same physical problem with a discrete approach and then with a continuum one. This procedure for 3D designs is applied to various domain geometries, to demonstrate its pertinence on high-resolution industrial cases. An algorithm searching for the best printing direction, exploring the solid angle, is also described and validated; the surface-shaped presentation of the result allows immediate understanding of the influence of the discrete problem parameters, while its running time is much lower than a unique continuum optimization simulation, which proves the attractiveness of the method. In the three examples studied, the procedure outputs exhibit greater printability than the ones produced by traditional methods in each of the printing direction tested, albeit responsibility is left to the final user to choose his best trade-off. Furthermore, the unprintable zones are readily displayed to be either reworked or supported. Explanations about increase of convergence likelihood on discrete structures despite the geometry complexity of an industrial application are also provided and demonstrated. 相似文献
103.
在EAST 快控电源中采用瞬时环流反馈引入虚拟电阻的均流控制策略,可大大增加并联逆变器之间等效输出阻抗的实部,有效提高对环流低频分量的抑制能力。仿真和实验结果验证了该控制策略的可行性和有效性。 相似文献
104.
HEC1(癌症高表达蛋白)是纺锤体检查点控制、着丝粒功能、细胞存活的关键的有丝分裂调节器,与原发性乳腺癌的不良预后有关.筛选具有高亲和力的HEC1新型抑制剂对探索乳腺癌的靶向治疗具有重要意义.本文从结构多样性的化合物库中筛选HEC1抑制剂.通过对分子描述符的特征筛选,采用支持向量机(SVM)和随机森林(RF)方法分别对HEC1抑制剂和非抑制剂建立了分类模型.经对比, RF模型显示了更好的预测精度.我们采用RF模型对HEC1抑制剂进行了虚拟筛选,从“in-house”实体库筛选得到2个潜在的HEC1抑制剂分子.随后对筛出的化合物进行了体外活性实验,发现对乳腺癌细胞株MDA-MB-468和MDA-MB-231均有一定程度的抗肿瘤活性.研究结果表明,机器学习方法对于设计和虚拟筛选HEC1抑制剂有良好的效果. 相似文献
105.
106.
Shereena M. Arif John D. Holliday Peter Willett 《Journal of computer-aided molecular design》2009,23(9):655-668
Current systems for similarity-based virtual screening use similarity measures in which all the fragments in a fingerprint
contribute equally to the calculation of structural similarity. This paper discusses the weighting of fragments on the basis
of their frequencies of occurrence in molecules. Extensive experiments with sets of active molecules from the MDL Drug Data Report and the World of Molecular Bioactivity databases, using fingerprints encoding Tripos holograms, Pipeline Pilot ECFC_4 circular substructures and Sunset Molecular
keys, demonstrate clearly that frequency-based screening is generally more effective than conventional, unweighted screening.
The results suggest that standardising the raw occurrence frequencies by taking the square root of the frequencies will maximise
the effectiveness of virtual screening. An upper-bound analysis shows the complex interactions that can take place between
representations, weighting schemes and similarity coefficients when similarity measures are computed, and provides a rationalisation
of the relative performance of the various weighting schemes. 相似文献
107.
Markus H. J. Seifert 《Journal of computer-aided molecular design》2009,23(9):633-644
Target-specific optimization of scoring functions for protein–ligand docking is an effective method for significantly improving
the discrimination of active and inactive molecules in virtual screening applications. Its applicability, however, is limited
due to the narrow focus on, e.g., single protein structures. Using an ensemble of protein kinase structures, the publically
available directory of useful decoys ligand dataset, and a novel multi-factorial optimization procedure, it is shown here
that scoring functions can be tuned to multiple targets of a target class simultaneously. This leads to an improved robustness
of the resulting scoring function parameters. Extensive validation experiments clearly demonstrate that (1) virtual screening
performance for kinases improves significantly; (2) variations in database content affect this kind of machine-learning strategy
to a lesser extent than binary QSAR models, and (3) the reweighting of interaction types is of particular importance for improved
screening performance.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
108.
Ragothaman Yennamalli Naidu Subbarao Thorsten Kampmann Ross P. McGeary Paul R. Young Bostjan Kobe 《Journal of computer-aided molecular design》2009,23(6):333-341
Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment
to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational
changes in the E protein and is an essential step in the virus life cycle. In this study, we analyzed the pre-fusion and post-fusion
structures of the dengue virus E protein to identify potential novel sites that could bind small molecules, which could interfere
with the conformational transitions that mediate the fusion process. We used an in silico virtual screening approach combining
three different docking algorithms (DOCK, GOLD and FlexX) to identify compounds that are likely to bind to these sites. Seven
structurally diverse molecules were selected to test experimentally for inhibition of dengue virus propagation. The best compound
showed an IC50 in the micromolar range against dengue virus type 2.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
109.
A rapidly changing competitive landscape and dynamic customer expectations require manufacturing firms to seek flexibility in product development. Product concept flexibility (i.e., developing design options) and product prototype flexibility (i.e., creating working models) emerge as effective ways to quickly develop new products that meet competitive challenges and satisfy customer demands. Product concept flexibility enables firms to fully explore various product definitions and ideas. Product prototype flexibility allows firms to gather customers’ feedback and investigate design feasibility. Using data from 273 manufacturing firms, this research tests mediating, moderating, and additive models that relate product concept flexibility, product prototype flexibility, and customer satisfaction. The results indicate that firms with high product concept flexibility are more likely to benefit from prototype flexibility than firms with low product concept flexibility, and that product concept flexibility and product prototype flexibility act independently and additively to predict customer satisfaction. 相似文献
110.
A linear elliptic control problem with pointwise state constraints is considered. These constraints are given in the domain.
In contrast to this, the control acts only at the boundary. We propose a general concept using virtual control in this paper.
The virtual control is introduced in objective, state equation, and constraints. Moreover, additional control constraints
for the virtual control are investigated. An error estimate for the regularization error is derived as main result of the
paper. The theory is illustrated by numerical tests. 相似文献