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31.
Katritch V Byrd CM Tseitin V Dai D Raush E Totrov M Abagyan R Jordan R Hruby DE 《Journal of computer-aided molecular design》2007,21(10-11):549-558
Essential for viral replication and highly conserved among poxviridae, the vaccinia virus I7L ubiquitin-like proteinase (ULP) is an attractive target for development of smallpox antiviral drugs. At the same time, the I7L proteinase exemplifies several interesting challenges from the rational drug design perspective. In the absence of a published I7L X-ray structure, we have built a detailed 3D model of the I7L ligand binding site (S2-S2' pocket) based on exceptionally high structural conservation of this site in proteases of the ULP family. The accuracy and limitations of this model were assessed through comparative analysis of available X-ray structures of ULPs, as well as energy based conformational modeling. The 3D model of the I7L ligand binding site was used to perform covalent docking and VLS of a comprehensive library of about 230,000 available ketone and aldehyde compounds. Out of 456 predicted ligands, 97 inhibitors of I7L proteinase activity were confirmed in biochemical assays ( approximately 20% overall hit rate). These experimental results both validate our I7L ligand binding model and provide initial leads for rational optimization of poxvirus I7L proteinase inhibitors. Thus, fragments predicted to bind in the prime portion of the active site can be combined with fragments on non-prime side to yield compounds with improved activity and specificity. 相似文献
32.
Wagener M van Geerestein VJ 《Journal of chemical information and computer sciences》2000,40(2):280-292
Using decision trees, a model to discriminate between potential drugs and nondrugs has been developed. Compounds from the Available Chemical Directory and the World Drug Index databases were used as training set; the molecular structures were represented using extended atom types. The error rate on an independent validation data set is 17.4%. The number of false negatives can be reduced by penalizing the misclassification of drugs so that 92 out of 100 potential drugs are correctly recognized. At the same time, 34 out of 100 nondrugs are classified as potential drugs. The predictions of the model can be used to guide the purchase or selection of compounds for biological screening or the design of combinatorial libraries. The visualization of the generated models in the form of colored trees allowed us to identify a few, surprisingly simple features that explain the most significant differences between drugs and nondrugs in the training set: Just by testing the presence of hydroxyl, tertiary or secondary amino, carboxyl, phenol, or enol groups, already three quarters of all drugs could be correctly recognized. The nondrugs, on the other hand, are characterized by their aromatic nature with a low content of functional groups besides halogens. The general applicability of the model is shown by the predictions made for several Organon databases. 相似文献
33.
Cai M Stankova M Pond SJ Mayorov AV Perry JW Yamamura HI Trivedi D Hruby VJ 《Journal of the American Chemical Society》2004,126(23):7160-7161
Receptor-based signaling mechanisms are the primary source of cellular regulation. The superfamily of G protein-coupled receptors (GPCR) is the largest and most ubiquitous of the receptor-mediated processes. Desensitization of G-protein-coupled receptors is a fundamental mechanism regulating the cellular response to agonists. We have recently studied the agonist and antagonist of the human melanocortin receptors (hMC1, hMC3, hMC4, and hMC5 receptors), the human delta opioid receptor, and the human gluacagon receptor with the help of synthetic fluorescent labeled ligands and fluorescent protein-labeled beta-arrestin-receptors that shed new insight on cellular signaling and rapid screening of drugs in real time. It was demonstrated that stimulation of these receptors by the cognate agonist triggers the rapid internalization of ligand-receptor complexes, while the interaction of the receptor with antagonists does not follow this pathway. Furthermore, receptor internalization is dependent upon beta-arrestin, which has been shown to be responsible for the rapid desensitization of cAMP-signaling processes. 相似文献
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35.
Cholecystokinin analogues containing N-methyl amino acids were studied by reversed-phase high-performance liquid chromatography at reduced temperatures. A reduction in temperature to -17 degrees C led to lower efficiency, but at the same time separations of cis and trans isomers (and some impurities) were achieved. The velocity constants for cis-trans equilibria were calculated. 相似文献
36.
Martin Hruby Cestmir Konak Jan Kucka Miroslav Vetrik Sergey K. Filippov David Vetvicka Hana Mackova Goran Karlsson Katarina Edwards Blanka Rihova Karel Ulbrich 《Macromolecular bioscience》2009,9(10):1016-1027
Novel polymer micelles, prepared by self‐assembling thermoresponsive poly(N‐isopropylacrylamide)‐graft‐poly[N‐(2‐hydroxypropyl)methacrylamide] copolymers with hydrolytically degradable N‐glycosylamine groups between the polymer blocks are proposed for delivery of diagnostic and therapeutic radionuclides into solid tumors. The micelles are formed by fast heating of an aqueous solution of the copolymer to 37 °C. They have a hydrodynamic diameter of 128 nm (measured using dynamic light scattering) and slowly degrade during incubation in aqueous buffer at pH = 7.4. Labeling with both 131I and 90Y proceeds with high yields (>85%). The unlabeled polymers are not cytotoxic for any of the tested murine and human cell lines.
37.
Anti-beta-substituted gamma,delta-unsaturated amino acids have been synthesized via a novel design of the Eschenmoser-Claisen rearrangement. The rearrangement gives good isolated yields and excellent diastereoselectivity due to (Z)-N,O-ketene acetal formation and the pseudochairlike conformations of the reaction intermediates. Upon reductive hydrolysis, important novel amino acids and amino alcohols were synthesized for the first time via this methodology. 相似文献
38.
39.
Balakrishnan Karthikeyan Aswini Kumar Giri Victor J. Hruby 《Journal of Sol-Gel Science and Technology》2014,72(3):534-542
After the discovery of the ability of dipeptide self-assembly, numerous research activities have been reported on Phe–Phe dipeptide based nano-materials. However, entrapping peptide nanotubes in a silicate matrix has not been carefully studied. This paper reports on self-assembled Phe–Phe nanotubes entrapped in a silicate matrix derived by a simple, and modified acid mediated sol–gel approach. Here, interaction of silver nanoparticles with regained nanotubes from the silicate matrix is reported. Mass spectrometry data showed the self-assembly of peptide monomers. Scanning electron microscopy and transmission electron microscopy studies have been used to examine the shapes and sizes of the nano-structures, and the results provide a promising method for trapping peptide based nanotubes. UV–Visible spectra suggest that there are some effects of silicate environment around Phe–Phe NTs on its absorbance. Density functional calculations showed the probable type of interaction between peptide and Ag atoms. This study can be useful for future applications, which are based on immobilization strategy for drug carrying and sensing. 相似文献
40.
Ondrej Sedlacek Jan Kucka Frantisek Svec Martin Hruby 《Journal of separation science》2014,37(7):798-802
In this study, we demonstrate the preparation of a macroporous monolithic column containing anchored silver nanoparticles and its use for the elimination of excess radioiodine from the radiolabeled pharmaceutical. The poly(glycidyl methacrylate‐co‐ethylene dimethacrylate) monolith was first functionalized with cystamine and the free thiol groups liberated by reaction with borohydride. In‐house‐prepared silver nanoparticles were then attached by interaction with the surface thiols. The deiodization process was demonstrated with the commonly used radiopharmaceutical m‐iodobenzylguanidine labeled with radionuclide iodine‐125. 相似文献