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https://www.readbyqxmd.com/read/28742329/selecting-dna-encoded-chemical-library-against-non-immobilized-proteins-using-a-ligate-crosslink-purify-strategy
#1
Bingbing Shi, Yuqing Deng, Peng Zhao, Xiaoyu Li
DNA-encoded chemical library (DEL) has recently emerged and become an important technology platform in biomedical research and drug discovery. DELs containing large numbers of compounds can be prepared and selected against biological targets to discover novel ligands and inhibitors. In practice, DELs are usually selected against purified and immobilized proteins using the typical "bind-wash-elute" protocol; however, selection methods compatible with non-immobilized proteins would be able to greatly expand the target scope of DELs beyond purified proteins to more complex and biologically relevant targets...
July 25, 2017: Bioconjugate Chemistry
https://www.readbyqxmd.com/read/28742206/bioinformatics-analysis-of-rna-seq-data-revealed-critical-genes-in-colon-adenocarcinoma
#2
W-D Xi, Y-J Liu, X-B Sun, J Shan, L Yi, T-T Zhang
OBJECTIVE: RNA-seq data of colon adenocarcinoma (COAD) were analyzed with bioinformatics tools to discover critical genes in the disease. Relevant small molecule drugs, transcription factors (TFs) and microRNAs (miRNAs) were also investigated. MATERIALS AND METHODS: RNA-seq data of COAD were downloaded from The Cancer Genome Atlas (TCGA). Differential analysis was performed with package edgeR. False positive discovery (FDR) < 0.05 and |log2 (fold change)|>1 were set as the cut-offs to screen out differentially expressed genes (DEGs)...
July 2017: European Review for Medical and Pharmacological Sciences
https://www.readbyqxmd.com/read/28741898/development-of-a-new-structural-class-of-broadly-acting-hcv-non-nucleoside-inhibitors-leading-to-the-discovery-of-mk-8876
#3
Casey C McComas, Anandan Palani, Wei Chang, M Katharine Holloway, Charles A Lesburg, Peng Li, Nigel Liverton, Peter T Meinke, David B Olsen, Xuanjia Peng, Richard M Soll, Ajay Ummat, Jie Wu, Jin Wu, Nicolas Zorn, Steven W Ludmerer
Studies directed at developing a broadly acting non-nucleoside inhibitor of HCV NS5B led to the discovery of a novel structural class of 5-aryl benzofurans that simultaneously interact with both the palm I and palm II binding regions. An initial candidate was potent in vitro against HCV GT1a and GT1b replicons, and induced multi-log reductions in HCV viral load when orally dosed to chronic GT1 infected chimpanzees. However, in vitro potency losses against clinically relevant GT1a variants prompted a further effort to develop compounds with sustained potency across a broader array of HCV genotypes and mutants...
July 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28741876/discovery-of-novel-potent-muscarinic-m3-receptor-antagonists-with-proper-plasma-stability-by-structural-recombination-of-marketed-m3-antagonists
#4
Zuojuan Xiang, Jun Liu, Hongbin Sun, Xiaoan Wen
The marketed long-acting M3 antagonists for treatment of chronic obstructive pulmonary disease have inappropriate plasma stability (either overstable or excessively unstable), which causes substantial systemic exposure or poor patient compliance. To discover novel M3 antagonists with proper plasma stability, we synthesized and biologically evaluated a series of chiral quaternary ammonium salts of pyrrolidinol esters, which were designed by structural recombination of the marketed M3 antagonists. As a result, two novel potent M3 antagonists, (R/S)-3-[2-hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1,1-dimethylpyrrolidinium bromides (1 a: Ki =0...
July 25, 2017: ChemMedChem
https://www.readbyqxmd.com/read/28741496/targeting-bcl-2-like-proteins-to-kill-cancer-cells
#5
REVIEW
Suzanne Cory, Andrew W Roberts, Peter M Colman, Jerry M Adams
Mutations that impair apoptosis contribute to cancer development and reduce the effectiveness of conventional anti-cancer therapies. These insights and understanding of how the B cell lymphoma (BCL)-2 protein family governs apoptosis have galvanized the search for a new class of cancer drugs that target its pro-survival members by mimicking their natural antagonists, the BCL-2 homology (BH)3-only proteins. Successful initial clinical trials of the BH3 mimetic venetoclax/ABT-199, specific for BCL-2, have led to its recent licensing for refractory chronic lymphocytic leukemia and to multiple ongoing trials for other malignancies...
August 2016: Trends in Cancer
https://www.readbyqxmd.com/read/28741255/genetics-of-schizophrenia-ready-to-translate
#6
REVIEW
Claire Foley, Aiden Corvin, Shigeki Nakagome
PURPOSE OF REVIEW: This is an era where we have significantly advanced the understanding of the genetic architecture of schizophrenia. In this review, we consider how this knowledge may translate into advances that will improve patient care. RECENT FINDINGS: Large-scale genome-wide association studies (GWAS) have identified more than a hundred loci each making a small contribution to illness risk. Meta-analysis of copy number variants (CNVs) in the Psychiatric Genomics Consortium (PGC) dataset has confirmed that some variants have a moderate or large impact on risk, although these are rare in the population...
September 2017: Current Psychiatry Reports
https://www.readbyqxmd.com/read/28741130/epigenetic-involvement-in-etiopathogenesis-and-implications-in-treatment-of-systemic-lupus-erythematous
#7
REVIEW
Arron Munggela Foma, Saeed Aslani, Jafar Karami, Ahmadreza Jamshidi, Mahdi Mahmoudi
BACKGROUND: Recent researches in the field of genetics have extended our knowledge through the discovery of genetic factors associated with autoimmune diseases (AID). Genetics by itself, however, cannot elucidate all the uncertainties encountered in the etiopathology of AID. On the other hand, incomplete harmony in the prevalence of AID in identical twins suggests that non-genetic factors may play an important role in determining the disease susceptibility. Besides, epigenetics, which is defined by changes in gene expression without a corresponding change in the DNA sequences, has come in to provide new awareness in the disease etiopathology by bridging the genetic and epigenetic factors...
July 24, 2017: Inflammation Research: Official Journal of the European Histamine Research Society ... [et Al.]
https://www.readbyqxmd.com/read/28740747/in-vitro-assessment-of-anti-proliferative-effect-induced-by-%C3%AE-mangostin-from-cratoxylum-arborescens-on-hela-cells
#8
Aisha I El Habbash, Najihah Mohd Hashim, Mohamed Yousif Ibrahim, Maizatulakmal Yahayu, Fatima Abd Elmutaal Omer, Mashitoh Abd Rahman, Noraziah Nordin, Gwendoline Ee Cheng Lian
Natural medicinal products possess diverse chemical structures and have been an essential source for drug discovery. Therefore, in this study, α-mangostin (AM) is a plant-derived compound was investigated for the apoptotic effect on human cervical cancer cells (HeLa). The cytotoxic effects of AM on the viability of HeLa and human normal ovarian cell line (SV40) were evaluated by using MTT assay. Results showed that AM inhibited HeLa cells viability at concentration- and time-dependent manner with IC50 value of 24...
2017: PeerJ
https://www.readbyqxmd.com/read/28738772/molecular-docking-and-drug-discovery-in-%C3%AE-adrenergic-receptors
#9
Santiago Vilar, Eduardo Sobarzo-Sánchez, Lourdes Santana, Eugenio Uriarte
Evolution in computer engineering, availability of increasing amounts of data and the development of new and fast docking algorithms and software have led to improved molecular simulations with crucial applications in virtual high-throughput screening and drug discovery. Moreover, analysis of protein-ligand recognition through molecular docking has become a valuable tool in drug design. In this review, we focus on the applicability of molecular docking on a particular class of G protein-coupled receptors: the β-adrenergic receptors, which are relevant targets in clinic for the treatment of asthma and cardiovascular diseases...
July 24, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28738771/fumitremorgins-and-relatives-from-tremorgenic-compounds-to-valuable-anti-cancer-drugs
#10
Wolf-Rainer Abraham
BACKGROUND: Fumitremorgins are mycotoxins but can also inhibit cancer cells and reverse their drug resistance. OBJECTIVE: The bioactivity of prenylated cyclo-Trp-Pro dipeptides and their derivatives concerning their application in anti-cancer therapies will be discussed. METHOD: Reports on the discovery and assessment of this class of fungal compounds are compiled from literature using Google Scholar and PubMed. The bioactivities of the natural compounds are discussed with the aim of their improvement for cancer therapy...
July 24, 2017: Current Medicinal Chemistry
https://www.readbyqxmd.com/read/28738394/the-contribution-of-adult-hippocampal-neurogenesis-to-the-progression-of-psychiatric-disorders
#11
Rachel A Kohman, Justin S Rhodes
New neurons are continuously formed in the adult hippocampus of the human, nonhuman primate, and rodent throughout life though rates of neurogenesis precipitously decline with age to near zero levels at the end of the natural life span. Since its discovery in the 1960s, a large number of studies have documented numerous environmental and genetic factors which regulate adult neurogenesis. Chief among the positive regulators of neurogenesis are exercise and antidepressant drugs. Chief among the negative regulators of neurogenesis besides age are stress and inflammation...
2017: Modern Trends in Pharmacopsychiatry
https://www.readbyqxmd.com/read/28738214/plasmodium-falciparum-in%C3%A2-vitro-continuous-culture-conditions-a-comparison-of-parasite-susceptibility-and-tolerance-to-anti-malarial-drugs-throughout-the-asexual-intra-erythrocytic-life-cycle
#12
Sandra Duffy, Vicky M Avery
The continuous culture of Plasmodium falciparum is often seen as a means to an end, that end being to probe the biology of the parasite in question, and ultimately for many in the malaria drug discovery arena, to identify means of killing the parasite in order to treat malaria. In vitro continuous culture of Plasmodium falciparum is a fundamental requirement when undertaking malaria research where the primary objectives utilise viable parasites of a desired lifecycle stage. This investigation, and resulting data, compared the impact culturing Plasmodium falciparum long term (4 months) in different environmental conditions had on experimental outcomes and thus conclusions...
July 15, 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/28737935/the-current-state-of-peptide-drug-discovery-back-to-the-future
#13
Antoine Henninot, James C Collins, John M Nuss
Over the last decade, peptide drug discovery has experienced a revival of interest and scientific momentum, as the pharmaceutical industry has come to appreciate the role that peptide therapeutics can play in addressing unmet medical needs, and how this class of compounds can be an excellent complement or even preferable alternative to small molecule and biological therapeutics. In this perspective we give a concise description of the recent progress in peptide drug discovery in a holistic manner, highlighting enabling technological advances affecting nearly every aspect of this field: from lead discovery, to synthesis and optimization, to peptide drug delivery...
July 24, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28737888/discovery-of-novel-proline-based-neuropeptide-ff-receptor-antagonists
#14
Thuy Nguyen, Ann M Decker, Tiffany L Langston, Kelly M Mathews, Justin N Siemian, Jun-Xu Li, Danni L Harris, Scott P Runyon, Yanan Zhang
The neuropeptide FF (NPFF) system has been implicated in a number of physiological processes including modulating the pharmacological activity of opioid analgesics and several other classes of drugs of abuse. In this study, we report the discovery of a novel proline scaffold with antagonistic activity at the NPFF receptors through a high throughput screening campaign using a functional calcium mobilization assay. Focused structure-activity relationship studies on the initial hit 1 have resulted in several analogs with calcium mobilization potencies in the submicromolar range and modest selectivity for the NPFF1 receptor...
July 24, 2017: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/28737449/molecular-docking-studies-of-fused-coumarin-derivatives-as-inhibitors-of-glcn-6
#15
Sevdije Govori, Arben Haziri, Kastriot Ademi, Nexhat Neziraj
The biological activity of heterocyclic compounds depends on their structure, the type of hetero atoms in the ring and on the type of substituents present. In this paper, some heterocyclic compounds with coumarin moieties S1-S5 and novobiocin known as coumarin antibiotic were subjected to the molecular docking studies as important tools for drug discovery. Glucosamine-6-phosphate synthase is selected as a suitable target in this study. In silico studies reveal that all synthesized compounds S1-S5 are good inhibitors of GlcN-6 and the docking results are in agreement with in vitro antibacterial evaluation of compounds S1-S5...
July 24, 2017: Journal of Environmental Science and Health. Part A, Toxic/hazardous Substances & Environmental Engineering
https://www.readbyqxmd.com/read/28737187/recent-advances-in-asymmetric-total-synthesis-of-prostaglandins
#16
REVIEW
Haihui Peng, Fen-Er Chen
Prostaglandins (PGs) are a series of hormone-like chemical messengers and play a critical role in regulating physiological activity. The diversified therapeutic activities and complex molecular architectures of PGs have attracted special attention, and huge progress has been made in asymmetric total synthesis and discovery of pharmaceutically useful drug candidates. In the last 10 years, several powerful syntheses have emerged as new solutions to the problem of building PGs and represent major breakthroughs in this area...
July 24, 2017: Organic & Biomolecular Chemistry
https://www.readbyqxmd.com/read/28737040/potential-of-small-molecule-fungal-metabolites-in-antiviral-chemotherapy
#17
Biswajit G Roy
Various viral diseases, such as acquired immunodeficiency syndrome, influenza, and hepatitis, have emerged as leading causes of human death worldwide. Scientific endeavor since invention of DNA-dependent RNA polymerase of pox virus in 1967 resulted in better understanding of virus replication and development of various novel therapeutic strategies. Despite considerable advancement in every facet of drug discovery process, development of commercially viable, safe, and effective drugs for these viruses still remains a big challenge...
July 23, 2017: Antiviral Chemistry & Chemotherapy
https://www.readbyqxmd.com/read/28737021/infection-therapy-the-problem-of-drug-resistance-and-possible-solutions
#18
Harald Brüssow
The rising antibiotic resistance in major bacterial pathogens together with the breakdown of the antibiotic discovery platform creates a critical situation for infection therapy. Recent developments reviving new antibiotic discovery from defining chemical rules for membrane-passing compounds to isolation chips for soil bacteria and exploring the human microbiome for antibiotic-producing bacteria are discussed. The potential of bacteriocins, tailocins, phage lysins, phages, probiotics and commensal blends as alternatives to antibiotics is evaluated...
July 24, 2017: Microbial Biotechnology
https://www.readbyqxmd.com/read/28736931/genetic-variants-in-hsd17b3-smad3-and-ipo11-impact-circulating-lipids-in-response-to-fenofibrate-in-individuals-with-type-2-diabetes
#19
Daniel M Rotroff, Sonja S Pijut, Skylar W Marvel, John R Jack, Tammy M Havener, Aurora Pujol, Agatha Schluter, Greg A Graf, Henry N Ginsberg, Hetal S Shah, He Gao, Mario-Luca Morieri, Alessandro Doria, Josyf C Mychaleckyi, Howard L McLeod, John B Buse, Michael J Wagner, Alison A Motsinger-Reif
Individuals with type 2 diabetes (T2D) and dyslipidemia are at an increased risk of cardiovascular disease. Fibrates are a class of drugs prescribed to treat dyslipidemia, but variation in response has been observed. To evaluate common and rare genetic variants that impact lipid responses to fenofibrate in statin-treated T2D patients, we examined lipid changes in response to fenofibrate therapy using genome-wide association(GWA). Associations were followed-up using gene expression studies in mice. Common variants in SMAD3 and IPO11 were marginally associated with lipid changes in black subjects(p<5x10(-6) )...
July 24, 2017: Clinical Pharmacology and Therapeutics
https://www.readbyqxmd.com/read/28736757/malaria-parasite-proteins-involved-in-nutrient-channels-at-the-host-erythrocyte-membrane-advances-and-questions-for-future-research
#20
S Chalapareddy, S A Desai
Erythrocytes infected malaria parasites have increased permeability to nutrients and other solutes, as mediated by an unusual ion channel known as the plasmodial surface anion channel (PSAC). Although the increased permeability of infected erythrocytes was identified more than 70 years ago and subsequently characterized with tracer studies, its mechanism and role in parasite biology remained unclear until the introduction of patch-clamp methods and high-throughput screening technologies. These methods discovered and implicated PSAC as the primary mechanism, determined that this channel is essential for parasite development, led to identification of the channel's genes, and stimulated antimalarial drug discovery against this target...
March 2017: Int J Curr Multidiscip Stud
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