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161.
Comparative molecular field analysis of protein tyrosine phosphatase low-molecular-weight substrates
A set of 25 low-molecular-weight substrates for protein tyrosine phosphatase PTP1 has been investigated by comparative molecular field analysis (CoMFA). The quality of the model was assessed by cross-validations, predictions for a test set of substrates, bootstrapping, randomization of biological data, grid characteristics tests, and comparison with the X-ray-determined binding site of a closely related enzyme. The CoMFA study provides new insight into the steric and electrostatic factors influencing binding around the active site in protein tyrosine phosphatase and complement existing information available from X-ray data. 相似文献
162.
In order to discover the novel anticonvulsant drugs, pharmacophore screening of the anticonvulsant inhibitors was enforced. Genetic Algorithm with Linear Assignment for Hypermolecular Alignment of Datasets (GALAHAD) and Comparative Molecular Field Analysis (CoMFA) studies were combined to implement our research. Firstly, multiple models were generated using GALAHAG based on high active molecules. Secondly, several of them were validated using the CoMFA study. Finally, a good values of q2 from training set and promising predictive power from test set were obtained based on one model simutaneously. One model had been selected as the most reasonable pharmacophore model. The results of the CoMFA study based on the model 1 suggested that both steric and electrostatic interactions played important roles. 相似文献
163.
Phosphoinositide-dependent protein kinase-1 (PDK1) is a Ser/Thr kinase which phosphorylates and activates members of the AGC
kinase group known to control processes such as tumor cell growth, protection from apoptosis, and tumor angiogenesis. In this
paper, CoMFA and CoMSIA studies were carried out on a training set of 56 conformationally rigid indolinone inhibitors of PDK1.
Predictive 3D QSAR models, established using atom fit alignment rule based on crystallographic-bound conformation, had cross-validated
(r
cv2) values of 0.738 and 0.816 and non-cross-validated (r
ncv2) values of 0.912 and 0.949 for CoMFA and CoMSIA models, respectively. The predictive ability of the CoMFA and CoMSIA models
was determined using a test set of 14 compounds, which gave predictive correlation coefficients (r
pred2) of 0.865 and 0.837, respectively. Structure-based interpretation of the CoMFA and CoMSIA field properties provided further
insights for the rational design of new PDK1 inhibitors.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
164.
Use of the hydrogen bond potential function in a comparative molecular field analysis (CoMFA) on a set of benzodiazepines 总被引:1,自引:0,他引:1
Ki Hwan Kim Giovanni Greco Ettore Novellino Carlo Silipo Antonio Vittoria 《Journal of computer-aided molecular design》1993,7(3):263-280
Summary The results of the GRID-Comparative Molecular Field Analysis (CoMFA) were compared with those of the SYBYL-CoMFA in a study of benzodiazepines. The results demonstrate that the hydrogen bonding function using the GRID H2O probe in a CoMFA can successfully describe the hydrophobic effects of substituents without any bias or preconcept of their effects in the development. 相似文献
165.
A panel of 92 catechol-O-methyltransferase (COMT) inhibitors was used to examine the molecular interactions affecting their biological activity. COMT inhibitors are used as therapeutic agents in the treatment of Parkinson's disease, but there are limitations in the currently marketed compounds due to adverse side effects. This study combined molecular docking methods with three-dimensional structure-activity relationships (3D QSAR) to analyse possible interactions between COMT and its inhibitors, and to incite the design of new inhibitors. Comparative molecular field analysis (CoMFA) and GRID/GOLPE models were made by using bioactive conformations from docking experiments, which yielded q2 values of 0.594 and 0.636, respectively. The docking results, the COMT X-ray structure, and the 3D QSAR models are in agreement with each other. The models suggest that an interaction between the inhibitor's catechol oxygens and the Mg2+ ion in the COMT active site is important. Both hydrogen bonding with Lys144, Asn170 and Glu199, and hydrophobic contacts with Trp38, Pro174 and Leu198 influence inhibitor binding. Docking suggests that a large R1 substituent of the catechol ring can form hydrophobic contacts with side chains of Val173, Leu198, Met201 and Val203 on the COMT surface. Our models propose that increasing steric volume of e.g. the diethylamine tail of entacapone is favourable for COMT inhibitory activity. 相似文献
166.
The EC50 values for a training set of 66 ecdysteroids and 97 diacylhydrazines were measured in the ecdysteroid-responsive Drosophila melanogaster BII cell line, a prototypical homologous inducible gene expression system. Each of eight superimposition hypotheses for the folded diacylhydrazine conformation was evaluated and ranked on the basis of CoMFA and 4D-QSAR Q2 values for the training set and R2 values for a 52-member test set comprising randomly-chosen diacylhydrazines and chronologically-chosen ecdysteroids for which data became available after model construction. Both 4D-QSAR and CoMFA rate a common superimposition as the preferred one. Two additional superimpositions, with somewhat weaker 4D-QSAR and CoMFA consensus, nonetheless share several important topological features. The resultant QSAR models address the question of relative binding orientation of the two ligand families and can be useful as a virtual screen for new chemotypes. 相似文献
167.
Kristine Prendergast Kym Adams William J. Greenlee Robert B. Nachbar Arthur A. Patchett Dennis J. Underwood 《Journal of computer-aided molecular design》1994,8(5):491-512
Summary A systematic search has been used to derive a hypothesis for the receptor-bound conformation of A-II antagonists at the AT1 receptor. The validity of the pharmacophore hypothesis has been tested using CoMFA, which included 50 diverse A-II antagonists, spanning four orders of magnitude in activity. The resulting cross-validated R2 of 0.64 (conventional R2 of 0.76) is indicative of a good predictive model of activity, and has been used to estimate potency for a variety of non-peptidyl antagonists. The structural model for the non-peptide has been compared with respect to the natural substrate, A-II, by generating peptide to non-peptide overlays. 相似文献
168.
Ki Hwan Kim 《Journal of computer-aided molecular design》1993,7(1):71-82
Summary The applicability of the comparative molecular field analysis (CoMFA) approach to describe the nonlinear dependence of biological activity on lipophilicity in 3D quantitative structure-activity relationships (QSAR) has been demonstrated. The results indicate that the CoMFA approach is appropriate for describing nonlinear effects in 3D QSAR studies. 相似文献
169.
170.
Roy J. Vaz Larry R. McLean John T. Pelton 《Journal of computer-aided molecular design》1998,12(2):99-110
The binding mode of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-amidino-2-naphthyl)propanoic acid hydrochloride (DX-9065a, 4) to Factor Xa is examined using inhibition data for a series of analogs that have a hydrophobic group as well as basic or dibasic functionality. Comparative molecular field analysis is utilized on a series of DX-9065a analogs in a series of proposed alternative binding modes. A quantitative measure is provided that distinguishes between the proposed binding modes that describes how well the binding mode explains the structure-activity relationship or the best 3D QSAR agrees with the crystallographically determined binding mode. The best model is in agreement with recently available data [Brandstetter et al., J. Biol. Chem., 271 (1996) 29988]. The highest statistical correlation occurs with the second basic group accommodated in the vicinity of Glu97 and a hydrophobic group accommodated in the pocket defined by Phe174, Tyr99 and Trp215. Also, the best model arises when the conformation of the Glu97 side chain is modified such that an H-bond interaction is maintained with the inhibitor if possible. The model also shows a tightening of the S1 pocket as is shown in the recent data described above. 相似文献