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https://www.readbyqxmd.com/read/29774657/cheminformatics-in-drug-discovery-an-industrial-perspective
#1
REVIEW
Hongming Chen, Thierry Kogej, Ola Engkvist
Cheminformatics has established itself as a core discipline within large scale drug discovery operations. It would be impossible to handle the amount of data generated today in a small molecule drug discovery project without persons skilled in cheminformatics. In addition, due to increased emphasis on "Big Data", machine learning and artificial intelligence, not only in the society in general, but also in drug discovery, it is expected that the cheminformatics field will be even more important in the future...
May 18, 2018: Molecular Informatics
https://www.readbyqxmd.com/read/29769246/small-molecule-positive-allosteric-modulators-of-the-%C3%AE-2-adrenoceptor-isolated-from-dna-encoded-libraries
#2
Seungkirl Ahn, Biswaranjan Pani, Alem W Kahsai, Eva K Olsen, Gitte Husemoen, Mikkel Vestrgaard, Lei Jin, Shuai Zhao, Laura M Wingler, Paula K Rambarat, Rishabh K Simhal, Thomas T Xu, Lillian D Sun, Paul J Shim, Dean P Staus, Li-Yin Huang, Thomas Franch, Xin Chen, Robert J Lefkowitz
Conventional drug discovery efforts at the β2 -adrenoceptor (β2 AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique allosteric sites has potential for developing more specific drugs with fewer side effects than orthosteric ligands. Using our recently developed approach for screening G protein-coupled receptors (GPCRs) with DNA-encoded small molecule libraries, we have discovered and characterized the first β2 AR small molecule positive allosteric modulators (PAMs) - compound-6 [(R)-N-(4-amino-1-(4-(tert-butyl)phenyl)-4-oxobutan-2-yl)-5-(N-isopropyl-N-methylsulfamoyl)-2-((4-methoxyphenyl) thio)benzamide] and its analogs...
May 16, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29767362/microrna-expression-analysis-next-generation-sequencing
#3
Poching Liu
MicroRNAs are a class of small noncoding RNAs that function as regulators involving in many biological processes. The evaluation of miRNAs and their targets has been aided by miRNA expression profiling studies including multiplex PCR, microarrays, and recent next-generation sequencing tools. Next-generation sequencing has enabled us to profile thousands of genes in a single experiment and overcome the background signal and cross-hybridization issues of microarrays. Next-generation sequencing also allows for the simultaneous confirmation of known miRNAs and discovery of new miRNAs, and significantly reduces costs while providing billions of nucleotide information within a single experiment...
2018: Methods in Molecular Biology
https://www.readbyqxmd.com/read/29766788/microbial-genetic-screens-for-monitoring-protein-misfolding-associated-with-neurodegeneration-tools-for-identifying-disease-relevant-genes-and-for-screening-synthetic-and-natural-compound-libraries-for-the-discovery-of-potential-therapeutics
#4
Kalliopi Kostelidou, Ilias Matis, Georgios Skretas
Neurodegenerative diseases (ND) are a major threat to the aging population and the lack of a single preventive or disease-modifying agent only serves to increase their impact. In the past few years, protein misfolding and the subsequent formation of neurotoxic oligomeric/aggregated protein species have emerged as a unifying theme underlying the pathology of these complex diseases. Recently developed microbial genetic screens and selection systems for monitoring ND-associated protein misfolding have allowed the establishment of high-throughput assays for the identification of cellular factors and processes that are important mediators of ND-associated proteotoxicities...
May 15, 2018: Current Pharmaceutical Design
https://www.readbyqxmd.com/read/29764933/discovery-of-peroxisome-proliferator-activated-receptor-%C3%AE-ppar%C3%AE-activators-with-a-ligand-screening-system-using-a-human-ppar%C3%AE-expressing-cell-line
#5
Keisuke Tachibana, Tomohiro Yuzuriha, Ryotaro Tabata, Syohei Fukuda, Takashi Maegawa, Rika Takahashi, Keiichi Tanimoto, Hirofumi Tsujino, Kazuto Nunomura, Bangzhong Lin, Yoshiharu Matsuura, Toshiya Tanaka, Takao Hamakubo, Juro Js Sakai, Tatsuhiko Kodama, Tadayuki Kobayashi, Kenji Ishimoto, Hiroyuki Miyachi, Takefumi Doi
Peroxisome proliferator-activated receptor alpha (PPARα) is a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. PPARα is mainly expressed in the liver, where it activates fatty acid oxidation and lipoprotein metabolism and improves plasma lipid profiles. Therefore, PPARα activators are often used to treat patients with dyslipidemia. To discover additional PPARα activators as potential compounds for use in hypolipidemic drugs, here we established human hepatoblastoma cell lines with luciferase reporter expression from the promoters containing peroxisome proliferator responsive elements (PPRE) and tetracycline-regulated expression of full-length human PPARα to quantify the effects of chemical ligands on PPARα activity...
May 15, 2018: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/29764756/straightforward-hit-identification-approach-in-fragment-based-discovery-of-bromodomain-containing-protein-4-brd4-inhibitors
#6
Petro Borysko, Yurii S Moroz, Oleksandr V Vasylchenko, Vasyl V Hurmach, Anastasia Starodubtseva, Natalia Stefanishena, Kateryna Nesteruk, Sergey Zozulya, Ivan S Kondratov, Oleksandr O Grygorenko
A combination approach of a fragment screening and "SAR by catalog" was used for the discovery of bromodomain-containing protein 4 (BRD4) inhibitors. Initial screening of 3695-fragment library against bromodomain 1 of BRD4 using thermal shift assay (TSA), followed by initial hit validation, resulted in 73 fragment hits, which were used to construct a follow-up library selected from available screening collection. Additionally, analogs of inactive fragments, as well as a set of randomly selected compounds were also prepared (3 × 3200 compounds in total)...
May 9, 2018: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/29761826/computational-discovery-of-potent-drugs-to-improve-the-treatment-of-pyrazinamide-resistant-mycobacterium-tuberculosis-mutants
#7
Manaswini Jagadeb, Surya N Rath, Avinash Sonawane
Emergence of multi-drug resistance tuberculosis has become a serious health problem globally. Accumulation of mutations in the drug target led to the development of multi-drug resistant mycobacterial strains that have made most of the conventional drugs ineffective. Hence, there is desperate need for the development of new therapeutic strategies. Here, we focused on the analysis of mutations in Mycobacterium tuberculosis (Mtb) PncA (pyrazinamidase) that is responsible for resistance against first-line anti-tuberculosis pyrazinamide (PZA) drug...
May 15, 2018: Journal of Cellular Biochemistry
https://www.readbyqxmd.com/read/29759983/high-throughput-discovery-of-functional-disordered-regions-investigation-of-transactivation-domains
#8
Charles Nj Ravarani, Tamara Y Erkina, Greet De Baets, Daniel C Dudman, Alexandre M Erkine, M Madan Babu
Over 40% of proteins in any eukaryotic genome encode intrinsically disordered regions (IDRs) that do not adopt defined tertiary structures. Certain IDRs perform critical functions, but discovering them is non-trivial as the biological context determines their function. We present IDR-Screen, a framework to discover functional IDRs in a high-throughput manner by simultaneously assaying large numbers of DNA sequences that code for short disordered sequences. Functionality-conferring patterns in their protein sequence are inferred through statistical learning...
May 14, 2018: Molecular Systems Biology
https://www.readbyqxmd.com/read/29755970/how-to-achieve-better-results-using-pass-based-virtual-screening-case-study-for-kinase-inhibitors
#9
Pavel V Pogodin, Alexey A Lagunin, Anastasia V Rudik, Dmitry A Filimonov, Dmitry S Druzhilovskiy, Mark C Nicklaus, Vladimir V Poroikov
Discovery of new pharmaceutical substances is currently boosted by the possibility of utilization of the Synthetically Accessible Virtual Inventory (SAVI) library, which includes about 283 million molecules, each annotated with a proposed synthetic one-step route from commercially available starting materials. The SAVI database is well-suited for ligand-based methods of virtual screening to select molecules for experimental testing. In this study, we compare the performance of three approaches for the analysis of structure-activity relationships that differ in their criteria for selecting of "active" and "inactive" compounds included in the training sets...
2018: Frontiers in Chemistry
https://www.readbyqxmd.com/read/29755570/identification-of-a-novel-tumor-binding-peptide-for-lung-cancer-through-in-vitro-panning
#10
Babak Bakhshinejad, Habib Nasiri
Tumor-targeted therapies are playing growing roles in cancer research. The exploitation of these powerful therapeutic modalities largely depends on the discovery of tumor-targeting ligands. Phage display has proven a promising high throughput screening tool for the identification of novel specific peptides with high binding affinity to cancer cells. In the present study, we describe the use of phage display to isolate peptide ligands binding specifically to human lung cancer cells. Towards this goal, we screened a phage display library of 7-mer random peptides in-vitro on non-small cell lung carcinoma (A549) as the target cell...
2018: Iranian Journal of Pharmaceutical Research: IJPR
https://www.readbyqxmd.com/read/29753124/translation-of-innovative-chemistry-into-screening-libraries-an-exemplar-partnership-from-the-european-lead-factory
#11
Remy Morgentin, Mark Dow, Anthony Aimon, George Karageorgis, Tuomo Kalliokoski, Didier Roche, Stephen Marsden, Adam S Nelson
The identification of high-quality starting points for drug discovery is an enduring challenge in medicinal chemistry. Yet, the chemical space explored in discovery programmes tends be limited by the narrow toolkit of robust methods that are exploited in discovery workflows. The European Lead Factory (ELF) was established in 2013 to boost early-stage drug discovery within Europe. In this Feature, we describe an exemplar partnership that has led to the addition of 21 119 distinctive screening compounds to the ELF Joint European Compound Library...
May 9, 2018: Drug Discovery Today
https://www.readbyqxmd.com/read/29752505/jean-louis-petit-1674-1750-a-pioneer-anatomist-and-surgeon-and-his-contribution-to-orthopaedic-surgery-and-trauma-surgery
#12
REVIEW
Konstantinos Markatos, Georgios Androutsos, Marianna Karamanou, Georgios Tzagkarakis, Maria Kaseta, Andreas Mavrogenis
PURPOSE: The purpose of this review is to summarize the life and work of Jean-Louis Petit, his inventions, his discoveries, and his impact on the evolution of surgery of his era. METHOD: A thorough search of the literature was undertaken in PubMed and Google Scholar as well as in physical books in libraries to summarize current and classic literature on Petit. RESULTS: Jean-Louis Petit (1674-1750) was an eminent anatomist and surgeon of his era with an invaluable contribution to clinical knowledge, surgical technique, and instrumentation as well as innovative therapeutic modalities and basic scientific discoveries...
May 11, 2018: International Orthopaedics
https://www.readbyqxmd.com/read/29751047/identification-of-novel-bioinspired-synthetic-mosquito-repellents-by-combined-ligand-based-screening-and-obp-structure-based-molecular-docking
#13
Trias Thireou, Georgia Kythreoti, Katerina E Tsitsanou, Konstantinos Koussis, Christina E Drakou, Julie Kinnersley, Thomas Kröber, Patrick M Guerin, Jing-Jiang Zhou, Kostas Iatrou, Elias Eliopoulos, Spyros E Zographos
In this work we report a fast and efficient virtual screening protocol for discovery of novel bioinspired synthetic mosquito repellents with lower volatility and, in all likelihood, increased protection time as compared with their plant-derived parental compounds. Our screening protocol comprises two filtering steps. The first filter is based on the shape and chemical similarity to known plant-derived repellents, whereas the second filter is based on the predicted similarity of the ligand's binding mode to the Anopheles gambiae odorant binding protein (AgamOBP1) relative to that of DEET and Icaridin to the same OBP...
May 8, 2018: Insect Biochemistry and Molecular Biology
https://www.readbyqxmd.com/read/29748676/guiding-principles-for-peptide-nanotechnology-through-directed-discovery
#14
REVIEW
A Lampel, R V Ulijn, T Tuttle
Life's diverse molecular functions are largely based on only a small number of highly conserved building blocks - the twenty canonical amino acids. These building blocks are chemically simple, but when they are organized in three-dimensional structures of tremendous complexity, new properties emerge. This review explores recent efforts in the directed discovery of functional nanoscale systems and materials based on these same amino acids, but that are not guided by copying or editing biological systems. The review summarises insights obtained using three complementary approaches of searching the sequence space to explore sequence-structure relationships for assembly, reactivity and complexation, namely: (i) strategic editing of short peptide sequences; (ii) computational approaches to predicting and comparing assembly behaviours; (iii) dynamic peptide libraries that explore the free energy landscape...
May 11, 2018: Chemical Society Reviews
https://www.readbyqxmd.com/read/29745839/multi-target-drug-repositioning-by-bipartite-block-wise-sparse-multi-task-learning
#15
Limin Li, Xiao He, Karsten Borgwardt
BACKGROUND: Finding potential drug targets is a crucial step in drug discovery and development. Recently, resources such as the Library of Integrated Network-Based Cellular Signatures (LINCS) L1000 database provide gene expression profiles induced by various chemical and genetic perturbations and thereby make it possible to analyze the relationship between compounds and gene targets at a genome-wide scale. Current approaches for comparing the expression profiles are based on pairwise connectivity mapping analysis...
April 24, 2018: BMC Systems Biology
https://www.readbyqxmd.com/read/29744712/next-generation-sequencing-library-preparation-method-for-identification-of-rna-viruses-on-the-ion-torrent-sequencing-platform
#16
Guiqian Chen, Yuan Qiu, Qingye Zhuang, Suchun Wang, Tong Wang, Jiming Chen, Kaicheng Wang
Next generation sequencing (NGS) is a powerful tool for the characterization, discovery, and molecular identification of RNA viruses. There were multiple NGS library preparation methods published for strand-specific RNA-seq, but some methods are not suitable for identifying and characterizing RNA viruses. In this study, we report a NGS library preparation method to identify RNA viruses using the Ion Torrent PGM platform. The NGS sequencing adapters were directly inserted into the sequencing library through reverse transcription and polymerase chain reaction, without fragmentation and ligation of nucleic acids...
May 9, 2018: Virus Genes
https://www.readbyqxmd.com/read/29740895/discovery-of-potent-polyphosphate-kinase-1-ppk1-inhibitors-using-structure-based-exploration-of-ppk1pharmacophoric-space-coupled-with-docking-analyses
#17
Rasha M Bashatwah, Mohammad A Khanfar, Sanaa K Bardaweel
Inorganic polyphosphate (polyP) is present in all living forms of life. Studied mainly in prokaryotes, polyP and its associated enzymes are vital in diverse metabolic activities, in some structural functions, and most importantly in stress responses. Bacterial species, including many pathogens, encode a homolog of a major polyP synthesis enzyme, Poly Phosphate Kinase (PPK) with 2 different genes coding for PPK1 and PPK2. Genetic deletion of the ppk1 gene leads to reduced polyP levels and the consequent loss of virulence and stress adaptation responses...
May 8, 2018: Journal of Molecular Recognition: JMR
https://www.readbyqxmd.com/read/29740519/repurposing-drugs-to-fast-track-therapeutic-agents-for-the-treatment-of-cryptococcosis
#18
Megan Truong, Leigh G Monahan, Dee A Carter, Ian G Charles
Many infectious diseases disproportionately affect people in the developing world. Cryptococcal meningitis is one of the most common mycoses in HIV-AIDS patients, with the highest burden of disease in sub-Saharan Africa. Current best treatment regimens still result in unacceptably high mortality rates, and more effective antifungal agents are needed urgently. Drug development is hampered by the difficulty of developing effective antifungal agents that are not also toxic to human cells, and by a reluctance among pharmaceutical companies to invest in drugs that cannot guarantee a high financial return...
2018: PeerJ
https://www.readbyqxmd.com/read/29740479/a-new-single-nucleotide-polymorphism-database-for-rainbow-trout-generated-through-whole-genome-resequencing
#19
Guangtu Gao, Torfinn Nome, Devon E Pearse, Thomas Moen, Kerry A Naish, Gary H Thorgaard, Sigbjørn Lien, Yniv Palti
Single-nucleotide polymorphisms (SNPs) are highly abundant markers, which are broadly distributed in animal genomes. For rainbow trout ( Oncorhynchus mykiss ), SNP discovery has been previously done through sequencing of restriction-site associated DNA (RAD) libraries, reduced representation libraries (RRL) and RNA sequencing. Recently we have performed high coverage whole genome resequencing with 61 unrelated samples, representing a wide range of rainbow trout and steelhead populations, with 49 new samples added to 12 aquaculture samples from AquaGen (Norway) that we previously used for SNP discovery...
2018: Frontiers in Genetics
https://www.readbyqxmd.com/read/29738823/when-fragments-link-a-bibliometric-perspective-on-the-development-of-fragment-based-drug-discovery
#20
REVIEW
Angelo K S Romasanta, Peter van der Sijde, Iina Hellsten, Roderick E Hubbard, Gyorgy M Keseru, Jacqueline van Muijlwijk-Koezen, Iwan J P de Esch
Fragment-based drug discovery (FBDD) is a highly interdisciplinary field, rich in ideas integrated from pharmaceutical sciences, chemistry, biology, and physics, among others. To enrich our understanding of the development of the field, we used bibliometric techniques to analyze 3642 publications in FBDD, complementing accounts by key practitioners. Mapping its core papers, we found the transfer of knowledge from academia to industry. Co-authorship analysis showed that university-industry collaboration has grown over time...
May 5, 2018: Drug Discovery Today
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