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Library Discovery

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https://www.readbyqxmd.com/read/28213771/a-novel-spiroindoline-targets-cell-cycle-and-migration-via-modulation-of-microtubule-cytoskeleton
#1
Naveen Kumar, Santanu Hati, Parthapratim Munshi, Subhabrata Sen, Seema Sehrawat, Shailja Singh
Natural product-inspired libraries of molecules with diverse architectures have evolved as one of the most useful tools for discovering lead molecules for drug discovery. In comparison to conventional combinatorial libraries, these molecules have been inferred to perform better in phenotypic screening against complicated targets. Diversity-oriented synthesis (DOS) is a forward directional strategy to access such multifaceted library of molecules. From a successful DOS campaign of a natural product-inspired library, recently a small molecule with spiroindoline motif was identified as a potent anti-breast cancer compound...
February 17, 2017: Molecular and Cellular Biochemistry
https://www.readbyqxmd.com/read/28212015/discovery-and-preclinical-characterization-of-3-4-4-chlorophenyl-7-fluoroquinoline-3-yl-sulfonyl-benzonitrile-a-novel-non-acetylenic-metabotropic-glutamate-receptor-5-mglur5-negative-allosteric-modulator-for-psychiatric-indications
#2
János Galambos, Attila Bielik, Mikhail Krasavin, Zoltán Orgován, György Domány, Katalin Nógrádi, Gábor Wágner, György T Balogh, Zoltán Béni, János Koti, Zoltán Szakács, Amrita Bobok, Sándor Kolok, Mónika L Miko-Bakk, Mónika Vastag, Katalin Sághy, Judit Laszy, Attila Sándor Halász, Ottilia Balázs, Krisztina Gál, István Greiner, Zsolt Szombathelyi, György M Keserű
Negative allosteric modulators (NAM) of metabotropic glutamate receptor 5 (mGluR5) have been implicated as potential pharmacotherapy for a number of psychiatric diseases including anxiety and depression. Most of the mGluR5 NAM clinical candidates can be characterized by the central acetylenic moiety that connects the terminal pharmacophores. Identification of a sulfoquinoline hit via high throughput screening (HTS) followed by optimization provided a 4-phenyl-3-aryl-sulfoquinoline lead compound with the minimal pharmacophore...
February 17, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28199790/an-integrated-microfluidic-processor-for-dna-encoded-combinatorial-library-functional-screening
#3
Andrew B MacConnell, Alexander K Price, Brian M Paegel
DNA-encoded synthesis is rekindling interest in combinatorial compound libraries for drug discovery and in technology for automated and quantitative library screening. Here, we disclose a microfluidic circuit that enables whole-library functional screens of DNA-encoded compound beads. The device carries out library bead distribution into picoliter-scale assay reagent droplets, photochemical cleavage of compound from the bead, assay incubation, laser-induced fluorescence-based assay detection, and fluorescence-activated droplet sorting to isolate hits...
February 15, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28197631/repositioning-of-amprenavir-as-a-novel-extracellular-signal-regulated-kinase-2-inhibitor-and-apoptosis-inducer-in-mcf-7-human-breast-cancer
#4
Wenchun Jiang, Xin Li, Tongyu Li, Hailian Wang, Wei Shi, Ping Qi, Chunyang Li, Jie Chen, Jinku Bao, Guodong Huang, Yi Wang
Computational drug repositioning by virtually screening existing drugs for additional therapeutic usage could efficiently accelerate anticancer drug discovery. Herein, a library of 1447 Food and Drug Administration (FDA)-approved small molecule drugs was screened in silico for inhibitors of extracellular signal-regulated kinase 2 (ERK2). Then, in vitro kinase assay demonstrated amprenavir, a HIV-1 protease inhibitor, as a potential kinase inhibitor of ERK2. The in vivo kinase assay indicated that amprenavir could inhibit ERK2-mediated phosphorylation of BimEL at Ser69...
January 24, 2017: International Journal of Oncology
https://www.readbyqxmd.com/read/28197319/structure-based-design-of-non-natural-peptidic-macrocyclic-mcl-1-inhibitors
#5
Jeffrey W Johannes, Stephanie Bates, Carl Beigie, Matthew A Belmonte, John Breen, Shenggen Cao, Paolo A Centrella, Matthew A Clark, John W Cuozzo, Christoph E Dumelin, Andrew D Ferguson, Sevan Habeshian, David Hargreaves, Camil Joubran, Steven Kazmirski, Anthony D Keefe, Michelle L Lamb, Haiye Lan, Yunxia Li, Hao Ma, Scott Mlynarski, Martin J Packer, Philip B Rawlins, Daniel W Robbins, Haidong Shen, Eric A Sigel, Holly H Soutter, Nancy Su, Dawn M Troast, Haiyun Wang, Kate F Wickson, Chengyan Wu, Ying Zhang, Qiuying Zhao, Xiaolan Zheng, Alexander W Hird
Mcl-1 is a pro-apoptotic BH3 protein family member similar to Bcl-2 and Bcl-xL. Overexpression of Mcl-1 is often seen in various tumors and allows cancer cells to evade apoptosis. Here we report the discovery and optimization of a series of non-natural peptide Mcl-1 inhibitors. Screening of DNA-encoded libraries resulted in hit compound 1, a 1.5 μM Mcl-1 inhibitor. A subsequent crystal structure demonstrated that compound 1 bound to Mcl-1 in a β-turn conformation, such that the two ends of the peptide were close together...
February 9, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28196101/de-novo-assembly-characterization-and-annotation-for-the-transcriptome-of-sarcocheilichthys-sinensis
#6
Chuankun Zhu, Zhengjun Pan, Hui Wang, Guoliang Chang, Nan Wu, Huaiyu Ding
The Chinese lake gudgeon Sarcocheilichthys sinensis is a small cyprinid fish with great aquaculture potential both for its edible and ornamental values. Nevertheless, available genomic and transcriptomic information for this fish is extremely deficient. In this study, a normalized cDNA library was constructed using 13 mixed tissues of an adult male S. sinensis, and was sequenced by the Illumina HiSeq2500 platform. De novo assembly was performed using 38,911,511 obtained clean reads, and a total of 147,282 unigenes with an average length of 900 bp were finally achieved...
2017: PloS One
https://www.readbyqxmd.com/read/28195700/discovery-and-characterization-of-a-potent-and-specific-peptide-ligand-targeting-endothelial-progenitor-cells-and-endothelial-cells-for-tissue-regeneration
#7
Dake Hao, Wenwu Xiao, Ruiwu Liu, Priyadarsini Kumar, YuanPei Li, Ping Zhou, Fuzheng Guo, Diana L Farmer, Kit S Lam, Fengshan Wang, Aijun Wang
Endothelial progenitor cells (EPCs) and endothelial cells (ECs) play a vital role in endothelialization and vascularization for tissue regeneration. Various EPC/EC targeting biomolecules have been investigated to improve tissue regeneration with limited success often due to their limited functional specificity and structural stability. One-Bead-One-Compound (OBOC) combinatorial technology is an ultra-high throughput chemical library synthesis and screening method suitable for ligand discovery against a wide range of biological targets, such as integrins...
February 14, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28194834/steering-siglec-sialic-acid-interactions-on-living-cells-using-bioorthogonal-chemistry
#8
Christian Büll, Torben Heise, Niek van Hilten, Johan F A Pijnenborg, Victor Bloemendal, Lotte Gerrits, Esther D Kers-Rebel, Tina Ritschel, Martijn H den Brok, Gosse J Adema, Thomas J Boltje
Sialic acid sugars that terminate cell-surface glycans form the ligands for the sialic acid binding immunoglobulin-like lectin (Siglec) family, which are immunomodulatory receptors expressed by immune cells. Interactions between sialic acid and Siglecs regulate the immune system, and aberrations contribute to pathologies like autoimmunity and cancer. Sialic acid/Siglec interactions between living cells are difficult to study owing to a lack of specific tools. Here, we report a glycoengineering approach to remodel the sialic acids of living cells and their binding to Siglecs...
February 14, 2017: Angewandte Chemie
https://www.readbyqxmd.com/read/28191850/discovery-of-an-inhibitor-of-the-proteasome-subunit-rpn11
#9
Christian Perez, Jing Li, Francesco Parlati, Matthieu Rouffet, Yuyong Ma, Andrew L Mackinnon, Tsui-Fen Chou, Raymond J Deshaies, Seth M Cohen
The proteasome plays a crucial role in degradation of normal proteins that happen to be constitutively or inducibly unstable, and in this capacity it plays a regulatory role. Additionally, it degrades abnormal/damaged/mutant/misfolded proteins, which serves a quality-control function. Inhibitors of the proteasome have been validated in the treatment of multiple myeloma, with several FDA-approved therapeutics. Rpn11 is a Zn(2+)-dependent metalloisopeptidase that hydrolyzes ubiquitin from tagged proteins that are trafficked to the proteasome for degradation...
February 13, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28190396/in-vitro-screening-of-an-fda-approved-library-against-eskape-pathogens
#10
Waleed Younis, Ahmed AbdelKhalek, Abdelrahman S Mayhoub, Mohamed N Seleem
Bacterial resistance to conventional antibiotics is an increasingly serious threat to public health worldwide that requires immediate exploration and the development of novel antimicrobial compounds. Drug repurposing is an inexpensive and untapped source of new antimicrobial leads, and it holds many attractive features warranting further attention for antimicrobial drug discovery. In an effort to repurpose drugs and explore new leads in the field of antimicrobial drug discovery, we performed a whole-cell screening assay of 1,600 Food and Drug Administration (FDA) approved drugs against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter cloacae (ESKAPE) pathogens...
February 9, 2017: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/28188816/a-chemical-genomics-approach-to-drug-reprofiling-in-oncology-antipsychotic-drug-risperidone-as-a-potential-adenocarcinoma-treatment
#11
Suzanne J Dilly, Andrew J Clark, Andrew Marsh, Daniel A Mitchell, Ricky Cain, Colin W G Fishwick, Paul C Taylor
Drug reprofiling is emerging as an effective paradigm for discovery of cancer treatments. Herein, an antipsychotic drug is immobilised using the Magic Tag(®) chemical genomics tool and screened against a T7 bacteriophage displayed library of polypeptides from Drosophila melanogaster, as a whole genome model, to uncover an interaction with a section of 17-β-HSD10, a proposed prostate cancer target. A computational study and enzyme inhibition assay with full length human 17-β-HSD10 identifies risperidone as a drug reprofiling candidate...
February 8, 2017: Cancer Letters
https://www.readbyqxmd.com/read/28188646/a-nonarchetypal-5-6-dihydro-2h-pyrano-3-2-g-indolizine-based-solution-solid-dual-emissive-aiegen-with-multicolor-tunability
#12
Ashutosh Raghuvanshi, Ajay K Jha, Ashutosh Sharma, Shahida Umar, Shachi Mishra, Ruchir Kant, Atul Goel
Screening of a chemical library of pyranones and their ring transformed fluorophores led to the discovery of a novel 5,6-dihydro-2H-pyrano[3,2-g]indolizine (DPI) class of the luminogen DPI 7, which exhibited unique solution-solid dual emission (SSDE) behaviour with emission color shift i.e. bright green fluorescence in liquid and strong red emission in the solid state. The AIE mechanism of these luminogens revealed a well-defined set of non-covalent interactions (CH…O and CH…N) particularly blocking the motion of C2-flexure leading to the restriction-of-intramolecular-vibrations (RIV) in the solid state...
February 11, 2017: Chemistry: a European Journal
https://www.readbyqxmd.com/read/28187957/discovery-of-n-2-aminoethyl-n-benzyloxyphenyl-benzamides-new-potent-trypanosoma-brucei-inhibitors
#13
Andriy Buchynskyy, J Robert Gillespie, Matthew A Hulverson, Joshua McQueen, Sharon A Creason, Ranae M Ranade, Nicole A Duster, Michael H Gelb, Frederick S Buckner
A phenotypic screen of a compound library for antiparasitic activity on Trypanosoma brucei, the causative agent of Human African Trypanosomiasis (HAT), led to the identification of N-(2-aminoethyl)-N-phenyl benzamides as a starting point for hit-to-lead medicinal chemistry. Eighty two analogues were prepared, which led to the identification of a set of highly potent N-(2-aminoethyl)-N-benzyloxyphenyl benzamides with the most potent compound 73 having an in vitro EC50=0.001μM. The compounds displayed drug-like properties when tested in a number of in vitro assays...
November 12, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28186401/chemoproteomic-screening-of-covalent-ligands-reveals-uba5-as-a-novel-pancreatic-cancer-target
#14
Allison M Roberts, David K Miyamoto, Tucker R Huffman, Leslie A Bateman, Ashley N Ives, David Akopian, Martin J Heslin, Carlo M Contreras, Michael Rape, Christine F Skibola, Daniel K Nomura
Chemical genetic screening of small-molecule libraries has been a promising strategy for discovering unique and novel therapeutic compounds. However, identifying the targets of lead molecules that arise from these screens has remained a major bottleneck in understanding the mechanism of action of these compounds. Here, we have coupled the screening of a cysteine-reactive fragment-based covalent ligand library with an isotopic tandem orthogonal proteolysis-enabled activity-based protein profiling (isoTOP-ABPP) chemoproteomic platform to rapidly couple the discovery of lead small molecules that impair pancreatic cancer pathogenicity with the identification of druggable hotspots for potential cancer therapy...
February 15, 2017: ACS Chemical Biology
https://www.readbyqxmd.com/read/28185268/interventions-for-raising-breast-cancer-awareness-in-women
#15
REVIEW
Máirín O'Mahony, Harry Comber, Tony Fitzgerald, Mark A Corrigan, Eileen Fitzgerald, Elizabeth A Grunfeld, Maura G Flynn, Josephine Hegarty
BACKGROUND: Breast cancer continues to be the most commonly diagnosed cancer in women globally. Early detection, diagnosis and treatment of breast cancer are key to better outcomes. Since many women will discover a breast cancer symptom themselves, it is important that they are breast cancer aware i.e. have the knowledge, skills and confidence to detect breast changes and present promptly to a healthcare professional. OBJECTIVES: To assess the effectiveness of interventions for raising breast cancer awareness in women...
February 10, 2017: Cochrane Database of Systematic Reviews
https://www.readbyqxmd.com/read/28184219/identification-of-bacterial-surface-antigens-by-screening-peptide-phage-libraries-using-whole-bacteria-cell-purified-antisera
#16
Yun-Fei Hu, Dun Zhao, Xing-Long Yu, Yu-Li Hu, Run-Cheng Li, Meng Ge, Tian-Qi Xu, Xiao-Bo Liu, Hua-Yuan Liao
Bacterial surface proteins can be good vaccine candidates. In the present study, we used polyclonal antibodies purified with intact Erysipelothrix rhusiopthiae to screen phage-displayed random dodecapeptide and loop-constrained heptapeptide libraries, which led to the identification of mimotopes. Homology search of the mimotope sequences against E. rhusiopthiae-encoded ORF sequences revealed 14 new antigens that may localize on the surface of E. rhusiopthiae. When these putative surface proteins were used to immunize mice, 9/11 antigens induced protective immunity...
2017: Frontiers in Microbiology
https://www.readbyqxmd.com/read/28181080/madurastatin-b3-a-rare-aziridine-derivative-from-actinomycete-nocardiopsis-sp-ls150010-with-potent-anti-tuberculosis-activity
#17
Xinjun Zhang, Hongtao He, Rong Ma, Zengchun Ji, Qi Wei, Huanqin Dai, Lixin Zhang, Fuhang Song
Since the discovery of the first antibiotic, natural products have played an important role in chemistry, biology and medicine. To explore the potential of bioactive compounds from microbes isolated from the southeast of Tibet, China, a crude extract library was constructed and screened against Staphylococcus aureus. The strain Nocardiopsis sp. LS150010 was scaled up and subjected to further chemical studies, resulting in the identification of N-salicyloyl-2-aminopropan-1,3-diol (2) and its rare aziridine derivative, madurastatin B3 (1)...
February 8, 2017: Journal of Industrial Microbiology & Biotechnology
https://www.readbyqxmd.com/read/28168222/tgprelid-a-mitochondrial-protein-linked-to-multidrug-resistance-in-the-parasite-toxoplasma-gondii
#18
Victoria Jeffers, Edwin T Kamau, Ananth R Srinivasan, Jonathan Harper, Preethi Sankaran, Sarah E Post, Joseph M Varberg, William J Sullivan, Jon P Boyle
New drugs to control infection with the protozoan parasite Toxoplasma gondii are needed as current treatments exert toxic side effects on patients. Approaches to develop novel compounds for drug development include screening of compound libraries and targeted inhibition of essential cellular pathways. We identified two distinct compounds that display inhibitory activity against the parasite's replicative stage: F3215-0002, which we previously identified during a compound library screen, and I-BET151, an inhibitor of bromodomains, the "reader" module of acetylated lysines...
January 2017: MSphere
https://www.readbyqxmd.com/read/28168155/diversity-oriented-synthesis-of-natural-product-like-libraries-containing-a-3-methylbenzofuran-moiety-for-the-discovery-of-new-chemical-elicitors
#19
Xingrui He, Xia Chen, Songbo Lin, Xiaochang Mo, Pengyong Zhou, Zhihao Zhang, Yaoyao Lu, Yu Yang, Haining Gu, Zhicai Shang, Yonggen Lou, Jun Wu
Natural products are a major source of biological molecules. The 3-methylfuran scaffold is found in a variety of plant secondary metabolite chemical elicitors that confer host-plant resistance against insect pests. Herein, the diversity-oriented synthesis of a natural-product-like library is reported, in which the 3-methylfuran core is fused in an angular attachment to six common natural product scaffolds-coumarin, chalcone, flavone, flavonol, isoflavone and isoquinolinone. The structural diversity of this library is assessed computationally using cheminformatic analysis...
February 2017: ChemistryOpen
https://www.readbyqxmd.com/read/28163017/small-molecule-inhibitors-of-the-sox18-transcription-factor
#20
Frank Fontaine, Jeroen Overman, Mehdi Moustaqil, Sreeman Mamidyala, Angela Salim, Kamesh Narasimhan, Nina Prokoph, Avril A B Robertson, Linda Lua, Kirill Alexandrov, Peter Koopman, Robert J Capon, Emma Sierecki, Yann Gambin, Ralf Jauch, Matthew A Cooper, Johannes Zuegg, Mathias Francois
Pharmacological modulation of transcription factors (TFs) has only met little success over the past four decades. This is mostly due to standard drug discovery approaches centered on blocking protein/DNA binding or interfering with post-translational modifications. Recent advances in the field of TF biology have revealed a central role of protein-protein interaction in their mode of action. In an attempt to modulate the activity of SOX18 TF, a known regulator of vascular growth in development and disease, we screened a marine extract library for potential small-molecule inhibitors...
January 27, 2017: Cell Chemical Biology
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