共查询到20条相似文献,搜索用时 15 毫秒
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Numerous novel beta-lactamases and aminoglycoside-modifying enzymes with altered substrate profiles continue to be identified. Plasmid-mediated transmission of many of these enzymes readily occurs due to inclusion of the encoding genes in mobile gene cassettes. Recent crystallographic determinations of the structures of metallo-beta-lactamases and aminoglycoside-modifying enzymes provide the opportunity for the rational design of inhibitors. 相似文献
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Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes. 总被引:1,自引:0,他引:1 下载免费PDF全文
The three classes of enzymes which inactivate aminoglycosides and lead to bacterial resistance are reviewed. DNA hybridization studies have shown that different genes can encode aminoglycoside-modifying enzymes with identical resistance profiles. Comparisons of the amino acid sequences of 49 aminoglycoside-modifying enzymes have revealed new insights into the evolution and relatedness of these proteins. A preliminary assessment of the amino acids which may be important in binding aminoglycosides was obtained from these data and from the results of mutational analysis of several of the genes encoding aminoglycoside-modifying enzymes. Recent studies have demonstrated that aminoglycoside resistance can emerge as a result of alterations in the regulation of normally quiescent cellular genes or as a result of acquiring genes which may have originated from aminoglycoside-producing organisms or from other resistant organisms. Dissemination of these genes is aided by a variety of genetic elements including integrons, transposons, and broad-host-range plasmids. As knowledge of the molecular structure of these enzymes increases, progress can be made in our understanding of how resistance to new aminoglycosides emerges. 相似文献
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Samo Turk Andreja Kovač Audrey Boniface Julieanne M. Bostock Ian Chopra Didier Blanot Stanislav Gobec 《Bioorganic & medicinal chemistry》2009,17(5):1884-1889
The ATP-dependent Mur ligases (MurC, MurD, MurE and MurF) successively add l-Ala, d-Glu, meso-A2pm or l-Lys, and d-Ala-d-Ala to the nucleotide precursor UDP-MurNAc, and they represent promising targets for antibacterial drug discovery. We have used the molecular docking programme eHiTS for the virtual screening of 1990 compounds from the National Cancer Institute ‘Diversity Set’ on MurD and MurF. The 50 top-scoring compounds from screening on each enzyme were selected for experimental biochemical evaluation. Our approach of virtual screening and subsequent in vitro biochemical evaluation of the best ranked compounds has provided four novel MurD inhibitors (best IC50 = 10 μM) and one novel MurF inhibitor (IC50 = 63 μM). 相似文献
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James F. Blake Nicholas C. Kallan Dengming Xiao Rui Xu Josef R. Bencsik Nicholas J. Skelton Keith L. Spencer Ian S. Mitchell Richard D. Woessner Susan L. Gloor Tyler Risom Stefan D. Gross Matthew Martinson Tony H. Morales Guy P.A. Vigers Barbara J. Brandhuber 《Bioorganic & medicinal chemistry letters》2010,20(19):5607-5612
The discovery and optimization of a series of pyrrolopyrimidine based protein kinase B (Pkb/Akt) inhibitors discovered via HTS and structure based drug design is reported. The compounds demonstrate potent inhibition of all three Akt isoforms and knockdown of phospho-PRAS40 levels in LNCaP cells and tumor xenografts. 相似文献
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Germanas JP Wang S Miner A Hao W Ready JM 《Bioorganic & medicinal chemistry letters》2007,17(24):6871-6875
To identify novel inhibitors of tyrosinase, a fluorescent assay was developed which is suitable for high-throughput screening. In the assay, oxidation of the substrate by tyrosinase leads to the release of a fluorescent coumarin. Several small molecules were identified that inhibited mushroom tyrosinase in vitro and human tyrosinase in cell culture. These compounds may represent lead structures for therapies targeted at disorders of hyperpigmentation. 相似文献
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《Bioorganic & medicinal chemistry letters》2020,30(14):127261
Bruton tyrosine kinase (BTK) is an important target in oncology and (auto)immunity. Various BTK inhibitors have been approved or are currently in clinical development. A novel BTK inhibitor series was developed starting with a quinazoline core. Moving from a quinazoline to a quinoline core provided a handle for selectivity for BTK over EGFR and resulted in the identification of potent and selective BTK inhibitors with good potency in human whole blood assay. Furthermore, proof of concept of this series for BTK inhibition was shown in an in vivo mouse model using one of the compounds identified. 相似文献
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Hugh Y. Zhu Alan B. Cooper Jagdish Desai George Njoroge Paul Kirschmeier W. Robert Bishop Corey Strickland Alan Hruza Ronald J. Doll Viyyoor M. Girijavallabhan 《Bioorganic & medicinal chemistry letters》2010,20(3):1134-1136
The discovery of C-linked imidazole azaheptapyridine bridgehead FPT inhibitors is described. This novel class of compounds are sub nM FPT enzyme inhibitors with potent cellular inhibitory activities. This series also has reduced hERG activity versus previous N-linked imidazole series. X-ray of compound 10a bound to FTase revealed strong interaction between bridgehead imidazole 3N with catalytic zinc atom. 相似文献
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Li AR Zhang J Greenberg J Lee T Liu J 《Bioorganic & medicinal chemistry letters》2011,21(8):2472-2475
A series of benzothiazinone and benzooxazinone derivatives were discovered as SGLT2 inhibitors. The optimization led to the discovery of compounds 31 and 32, which exhibited similar potency and better SGLT1 selectivity compared to dapagliflozin. These compounds may provide novel promising scaffolds, which are different from phlorizin-based SGLT2 inhibitors. 相似文献
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Yibin Xiang Gary Asmussen Michael Booker Bradford Hirth John L. Kane Junkai Liao Kevin D. Noson Christopher Yee 《Bioorganic & medicinal chemistry letters》2009,19(21):6119-6121
Sphingosine kinase 1 (SK1) is an important enzyme that regulates the balance between ceramide and sphingosine-1-phosphate (S1P). Potent and novel SK1 inhibitors (6ag, 9ab and 12aa) have been discovered through a series of modifications of sphingosine (1), the substrate of this enzyme. 相似文献
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Kunz RK Rumfelt S Chen N Zhang D Tasker AS Bürli R Hungate R Yu V Nguyen Y Whittington DA Meagher KL Plant M Tudor Y Schrag M Xu Y Ng GY Hu E 《Bioorganic & medicinal chemistry letters》2008,18(18):5115-5117
Deregulation of the receptor tyrosine kinase c-Kit is associated with an increasing number of human diseases, including certain cancers and mast cell diseases. Interference of c-Kit signaling with multi-kinase inhibitors has been shown clinically to successfully treat gastrointestinal stromal tumors and mastocytosis. Targeted therapy of c-Kit activity may provide therapeutic advantages against off-target effects for non-oncology applications. A new structural class of c-Kit inhibitors is described, including in vitro c-Kit potency, kinase selectivity, and the observed binding mode. 相似文献
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Rai R Kolesnikov A Sprengeler PA Torkelson S Ton T Katz BA Yu C Hendrix J Shrader WD Stephens R Cabuslay R Sanford E Young WB 《Bioorganic & medicinal chemistry letters》2006,16(8):2270-2273
Structure-activity relationships and binding mode of novel heterocyclic factor VIIa inhibitors will be described. In these inhibitors, a highly basic 5-amidinoindole moiety has been successfully replaced with a less basic 5-aminopyrrolo[3,2-b]pyridine scaffold. 相似文献
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Kallan NC Spencer KL Blake JF Xu R Heizer J Bencsik JR Mitchell IS Gloor SL Martinson M Risom T Gross SD Morales TH Wu WI Vigers GP Brandhuber BJ Skelton NJ 《Bioorganic & medicinal chemistry letters》2011,21(8):2410-2414
A novel series of spirochromane pan-Akt inhibitors is reported. SAR optimization furnished compounds with improved enzyme potencies and excellent selectivity over the related AGC kinase PKA. Attempted replacement of the phenol hinge binder provided compounds with excellent Akt enzyme and cell activities but greatly diminished selectivity over PKA. 相似文献
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Alessandra Bartolozzi Asitha Abeywardane Todd Bosanac John A. Broadwater Zhidong Chen J. Matthew Hutzler John D. Huber Peter Nemoto Alan Olague Doris Riether Tom Simpson Hidenori Takahashi Lifen Wu Yunlong Zhang Renee M. Zindell 《Bioorganic & medicinal chemistry letters》2017,27(20):4652-4659
Structure activity relationship (SAR) investigation of an oxadiazole based series led to the discovery of several potent FLAP inhibitors. Lead optimization focused on achieving functional activity while improving physiochemical properties and reducing hERG inhibition. Several compounds with favorable in vitro and in vivo properties were identified that were suitable for advanced profiling. 相似文献
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Cliff C. Cheng Gerald W. Shipps Zhiwei Yang Binyuan Sun Noriyuki Kawahata Kyle A. Soucy Aileen Soriano Peter Orth Li Xiao Paul Mann Todd Black 《Bioorganic & medicinal chemistry letters》2009,19(23):6507-6514
The biotin carboxylase (AccC) is part of the multi-component bacterial acetyl coenzyme-A carboxylase (ACCase) and is essential for pathogen survival. We describe herein the affinity optimization of an initial hit to give 2-(2-chlorobenzylamino)-1-(cyclohexylmethyl)-1H-benzo[d]imidazole-5-carboxamide (1), which was identified using our proprietary Automated Ligand Identification System (ALIS).1 The X-ray co-crystal structure of 1 was solved and revealed several key interactions and opportunities for further optimization in the ATP site of AccC. Structure Based Drug Design (SBDD) and parallel synthetic approaches resulted in a novel series of AccC inhibitors, exemplified by (R)-2-(2-chlorobenzylamino)-1-(2,3-dihydro-1H-inden-1-yl)-1H-imidazo[4,5-b]pyridine-5-carboxamide (40). This compound is a potent and selective inhibitor of bacterial AccC with an IC50 of 20 nM and a MIC of 0.8 μg/mL against a sensitized strain of Escherichia coli (HS294 E. coli). 相似文献
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A small library of 19 compounds was designed based on unique structural features of PTP1b. Utilizing electrospray ionization mass spectrometry (ESI-MS) to provide binding information about complexes of enzyme and small molecule ligands, two classes of lead compounds were discovered. 相似文献