共查询到20条相似文献,搜索用时 15 毫秒
1.
Ze-Qiang Ma Sheng-Xue Xie Qing-Qing Huang Fa-Jun Nan Thomas D Hurley Qi-Zhuang Ye 《BMC structural biology》2007,7(1):84
Background
Methionine aminopeptidase is a potential target of future antibacterial and anticancer drugs. Structural analysis of complexes of the enzyme with its inhibitors provides valuable information for structure-based drug design efforts. 相似文献2.
Jing Cao Xian-Jin Xie Song Zhang Angelique Whitehurst Michael A White 《BMC bioinformatics》2009,10(1):5
Background
In high throughput screening, such as differential gene expression screening, drug sensitivity screening, and genome-wide RNAi screening, tens of thousands of tests need to be conducted simultaneously. However, the number of replicate measurements per test is extremely small, rarely exceeding 3. Several current approaches demonstrate that test statistics with shrinking variance estimates have more power over the traditional t statistic. 相似文献3.
Fabian Zanella Aranzazú Rosado Beatriz Garcia Amancio Carnero Wolfgang Link 《BMC cell biology》2009,10(1):14-10
Background
Independent luciferase reporter assays and fluorescent translocation assays have been successfully used in drug discovery for several molecular targets. We developed U2transLUC, an assay system in which luciferase and fluorescent read-outs can be multiplexed to provide a powerful cell-based high content screening method. 相似文献4.
Paulo S Monzani Stefano Trapani Otavio H Thiemann Glaucius Oliva 《BMC structural biology》2007,7(1):59
Background
Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) (EC 2.4.2.8) is a central enzyme in the purine recycling pathway. Parasitic protozoa of the order Kinetoplastida cannot synthesize purines de novo and use the salvage pathway to synthesize purine bases, making this an attractive target for antiparasitic drug design. 相似文献5.
Honglin Li Hailei Zhang Mingyue Zheng Jie Luo Ling Kang Xiaofeng Liu Xicheng Wang Hualiang Jiang 《BMC bioinformatics》2009,10(1):58
Background
Development of a fast and accurate scoring function in virtual screening remains a hot issue in current computer-aided drug research. Different scoring functions focus on diverse aspects of ligand binding, and no single scoring can satisfy the peculiarities of each target system. Therefore, the idea of a consensus score strategy was put forward. Integrating several scoring functions, consensus score re-assesses the docked conformations using a primary scoring function. However, it is not really robust and efficient from the perspective of optimization. Furthermore, to date, the majority of available methods are still based on single objective optimization design. 相似文献6.
Nicklas H Staunstrup Nynne Sharma Rasmus O Bak Lars Svensson Thomas K Petersen Lene Aarenstrup Karsten Kristiansen Lars Bolund Jacob Giehm Mikkelsen 《BMC biotechnology》2011,11(1):33
Background
Analogues of vitamin D3 are extensively used in the treatment of various illnesses, such as osteoporosis, inflammatory skin diseases, and cancer. Functional testing of new vitamin D3 analogues and formulations for improved systemic and topical administration is supported by sensitive screening methods that allow a comparative evaluation of drug properties. As a new tool in functional screening of vitamin D3 analogues, we describe a genomically integratable sensor for sensitive drug detection. This system facilitates assessment of the pharmacokinetic and pharmadynamic properties of vitamin D3 analogues. The tri-cistronic genetic sensor encodes a drug-sensoring protein, a reporter protein expressed from an activated sensor-responsive promoter, and a resistance marker. 相似文献7.
Anthony KG Strych U Yeung KR Shoen CS Perez O Krause KL Cynamon MH Aristoff PA Koski RA 《PloS one》2011,6(5):e20374
Background
In an effort to discover new drugs to treat tuberculosis (TB) we chose alanine racemase as the target of our drug discovery efforts. In Mycobacterium tuberculosis, the causative agent of TB, alanine racemase plays an essential role in cell wall synthesis as it racemizes L-alanine into D-alanine, a key building block in the biosynthesis of peptidoglycan. Good antimicrobial effects have been achieved by inhibition of this enzyme with suicide substrates, but the clinical utility of this class of inhibitors is limited due to their lack of target specificity and toxicity. Therefore, inhibitors that are not substrate analogs and that act through different mechanisms of enzyme inhibition are necessary for therapeutic development for this drug target.Methodology/Principal Findings
To obtain non-substrate alanine racemase inhibitors, we developed a high-throughput screening platform and screened 53,000 small molecule compounds for enzyme-specific inhibitors. We examined the ‘hits’ for structural novelty, antimicrobial activity against M. tuberculosis, general cellular cytotoxicity, and mechanism of enzyme inhibition. We identified seventeen novel non-substrate alanine racemase inhibitors that are structurally different than any currently known enzyme inhibitors. Seven of these are active against M. tuberculosis and minimally cytotoxic against mammalian cells.Conclusions/Significance
This study highlights the feasibility of obtaining novel alanine racemase inhibitor lead compounds by high-throughput screening for development of new anti-TB agents. 相似文献8.
Alexei Vazquez 《BMC systems biology》2009,3(1):81-6
Background
Identifying effective drug combinations that significantly improve over single agents is a challenging problem. Pairwise combinations already represent a huge screening effort. Beyond two drug combinations the task seems unfeasible. 相似文献9.
Background
The acetamidase of Mycobacterium smegmatis is a highly inducible enzyme. Expression of this enzyme is increased 100-fold when the substrate acetamide is present. The acetamidase gene is found immediately downstream of three open reading frames. Two of these are proposed to be involved in regulation. 相似文献10.
Antti Vasala Johanna Panula Monika Bollók Lutz Illmann Christian Hälsig Peter Neubauer 《Microbial cell factories》2006,5(1):8-6
Background
Shake flasks are widely used because of their low price and simple handling. Many researcher are, however, not aware of the physiological consequences of oxygen limitation and substrate overflow metabolism that occur in shake flasks. Availability of a wireless measuring system brings the possibilities for quality control and design of cultivation conditions. 相似文献11.
Thomas G Kristensen Jesper Nielsen Christian NS Pedersen 《Algorithms for molecular biology : AMB》2010,5(1):9
Background
The fingerprint of a molecule is a bitstring based on its structure, constructed such that structurally similar molecules will have similar fingerprints. Molecular fingerprints can be used in an initial phase of drug development for identifying novel drug candidates by screening large databases for molecules with fingerprints similar to a query fingerprint. 相似文献12.
Frédérique Fenneteau Jacques Turgeon Lucie Couture Véronique Michaud Jun Li Fahima Nekka 《Theoretical biology & medical modelling》2009,6(1):2-13
Background
The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate. 相似文献13.
Yukiko Yagi Kotaro Terada Takahisa Noma Kazunori Ikebukuro Koji Sode 《BMC bioinformatics》2007,8(1):11
Background
Peptide ligands have tremendous therapeutic potential as efficacious drugs. Currently, more than 40 peptides are available in the market for a drug. However, since costly and time-consuming synthesis procedures represent a problem for high-throughput screening, novel procedures to reduce the time and labor involved in screening peptide ligands are required. We propose the novel approach of 'in silico panning' which consists of a two-stage screening, involving affinity selection by docking simulation and evolution of the peptide ligand using genetic algorithms (GAs). In silico panning was successfully applied to the selection of peptide inhibitor for water-soluble quinoprotein glucose dehydrogenase (PQQGDH). 相似文献14.
Alessandro Siglioccolo Alessandro Paiardini Maria Piscitelli Stefano Pascarella 《BMC structural biology》2011,11(1):1-12
Background
Disrupting protein-protein interactions by small organic molecules is nowadays a promising strategy employed to block protein targets involved in different pathologies. However, structural changes occurring at the binding interfaces make difficult drug discovery processes using structure-based drug design/virtual screening approaches. Here we focused on two homologous calcium binding proteins, calmodulin and human centrin 2, involved in different cellular functions via protein-protein interactions, and known to undergo important conformational changes upon ligand binding.Results
In order to find suitable protein conformations of calmodulin and centrin for further structure-based drug design/virtual screening, we performed in silico structural/energetic analysis and molecular docking of terphenyl (a mimicking alpha-helical molecule known to inhibit protein-protein interactions of calmodulin) into X-ray and NMR ensembles of calmodulin and centrin. We employed several scoring methods in order to find the best protein conformations. Our results show that docking on NMR structures of calmodulin and centrin can be very helpful to take into account conformational changes occurring at protein-protein interfaces.Conclusions
NMR structures of protein-protein complexes nowadays available could efficiently be exploited for further structure-based drug design/virtual screening processes employed to design small molecule inhibitors of protein-protein interactions. 相似文献15.
16.
Background
Screening new lignocellulosic biomass pretreatments and advanced enzyme systems at process relevant conditions is a key factor in the development of economically viable lignocellulosic ethanol. Shake flasks, the reaction vessel commonly used for screening enzymatic saccharifications of cellulosic biomass, do not provide adequate mixing at high-solids concentrations when shaking is not supplemented with hand mixing. 相似文献17.
Cinzia Tarsia Alberto Danielli Francesca Florini Paolo Cinelli Stefano Ciurli Barbara Zambelli 《Biochimica et Biophysica Acta (BBA)/General Subjects》2018,1862(10):2245-2253
Background
Helicobacter pylori is a bacterium strongly associated with gastric cancer. It thrives in the acidic environment of the gastric niche of large portions of the human population using a unique adaptive mechanism that involves the catalytic activity of the nickel-dependent enzyme urease. Targeting urease represents a key strategy for drug design and H. pylori eradication.Method
Here, we describe a novel method to screen, directly in the cellular environment, urease inhibitors. A ureolytic Escherichia coli strain was engineered by cloning the entire urease operon in an expression plasmid and used to test in-cell urease inhibition with a high-throughput colorimetric assay. A two-plasmid system was further developed to evaluate the ability of small peptides to block the protein interactions that lead to urease maturation.Results
The developed assay is a robust cellular model to test, directly in the cell environment, urease inhibitors. The efficacy of a co-expressed peptide to affect the interaction between UreF and UreD, two accessory proteins necessary for urease activation, was observed. This event involves a process that occurs through folding upon binding, pointing to the importance of intrinsically disordered hot spots in protein interfaces.Conclusions
The developed system allows the concomitant screening of a large number of drug candidates that interfere with the urease activity both at the level of the enzyme catalysis and maturation.General significance
As inhibition of urease has the potential of being a global antibacterial strategy for a large number of infections, this work paves the way for the development of new candidates for antibacterial drugs. 相似文献18.
Isabella Faraoni Serena Laterza Davide Ardiri Claudia Ciardi Francesco Fazi Francesco Lo-Coco 《Journal of hematology & oncology》2012,5(1):1-5
Background
Gain-of-function mutations of tyrosine kinase FLT3 are frequently found in acute myeloid leukemia (AML). This has made FLT3 an important marker for disease diagnosis and a highly attractive target for therapeutic drug development. This study is intended to generate a sensitive substrate for assays of the FLT3 enzymatic activity.Methods
We expressed in Escherichia coli cells a glutathione S-transferase (GST) fusion protein designated GST-FLT3S, which contains a peptide sequence derived from an autophosphorylation site of FLT3. The protein was used to analyze tyrosine kinase activity of baculovirus-expressed FLT3 and crude cell extracts of bone marrow cells from AML patients. It was also employed to perform FLT3 kinase assays for FLT3 inhibitor screening.Results
GST-FLT3S in solution or on beads was strongly phosphorylated by recombinant proteins carrying the catalytic domain of wild type FLT3 and FLT3D835 mutants, with the latter exhibiting much higher activity and efficiency. GST-FLT3S was also able to detect elevated tyrosine kinase activity in bone marrow cell extracts from AML patients. A small-scale inhibitor screening led to identification of several potent inhibitors of wild type and mutant forms of FLT3.Conclusions
GST-FLT3S is a sensitive protein substrate for FLT3 assays. It may find applications in diagnosis of diseases related to abnormal FLT3 activity and in inhibitor screening for drug development. 相似文献19.
Background
High throughput screening (HTS) is one of the primary tools used to identify novel enzyme inhibitors. However, its applicability is generally restricted to targets that can either be expressed recombinantly or purified in large quantities.Methodology and Principal Findings
Here, we described a method to use activity-based probes (ABPs) to identify substrates that are sufficiently selective to allow HTS in complex biological samples. Because ABPs label their target enzymes through the formation of a permanent covalent bond, we can correlate labeling of target enzymes in a complex mixture with inhibition of turnover of a substrate in that same mixture. Thus, substrate specificity can be determined and substrates with sufficiently high selectivity for HTS can be identified. In this study, we demonstrate this method by using an ABP for dipeptidyl aminopeptidases to identify (Pro-Arg)2-Rhodamine as a specific substrate for DPAP1 in Plasmodium falciparum lysates and Cathepsin C in rat liver extracts. We then used this substrate to develop highly sensitive HTS assays (Z’>0.8) that are suitable for use in screening large collections of small molecules (i.e >300,000) for inhibitors of these proteases. Finally, we demonstrate that it is possible to use broad-spectrum ABPs to identify target-specific substrates.Conclusions
We believe that this approach will have value for many enzymatic systems where access to large amounts of active enzyme is problematic. 相似文献20.
Shuxing Zhang Kamal Kumar Xiaohui Jiang Anders Wallqvist Jaques Reifman 《BMC bioinformatics》2008,9(1):126