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https://www.readbyqxmd.com/read/29786944/design-synthesis-and-evaluation-of-a-novel-series-of-inhibitors-reversing-p-glycoprotein-mediated-multidrug-resistance
#1
Hesham Ghaleb, Huilan Li, Mutta Kairuki, Qianqian Qiu, Xinzhou Bi, Chunxia Liu, Chen Liao, Jieming Li, Kamal Hezam, Wenlong Huang, Hai Qian
Multidrug resistance (MDR) is still the main barrier to attaining effective results with chemotherapy. Discovery of new chemo-reversal agents is needed to overcome MDR. Our study focused on a better way to obtain novel drugs with triazole rings that have an MDR-reversal ability through click chemistry. Among 20 developed compounds, compound 19 had a minimal cytotoxic effect compared to tariquidar and verapamil (VRP) and showed a higher reversal activity than VRP through increased accumulation in K562/A02 cells...
May 22, 2018: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/29786716/unexpected-protonation-state-of-glu197-discovered-from-simulations-of-tacrine-in-butyrylcholinesterase
#2
Xiao Wan, Yuan Yao, Lei Fang, Junjun Liu
Butyrylcholinesterase (BChE) has been actively involved in drug discoveries from many fields for decades. In the crystal structure of the BChE-tacrine complex, there is an unanticipated formyl-proline molecule resolved very close to tacrine, raising an essential question on how reliable it is to apply the binding pose in a crystal structure to analyze related experimental observations, in which no formyl-proline is actually involved. In this study, by performing a series of 100 ns molecular dynamics simulations, we demonstrate that it is safe to employ the structural information from this crystal structure to analyze related experimental observations...
May 22, 2018: Physical Chemistry Chemical Physics: PCCP
https://www.readbyqxmd.com/read/29786562/application-of-hepatocyte-like-cells-to-enhance-hepatic-safety-risk-assessment-in-drug-discovery
#3
REVIEW
Dominic P Williams
Hepatic stress and injury from drugs continues to be a major concern within the pharmaceutical industry, leading to preclinical and clinical attrition precautionary warnings and post-market withdrawal of drugs. There is a requirement for more predictive and mechanistically accurate models to aid risk assessment. Primary human hepatocytes, subject to isolation stress, cryopreservation, donor-to-donor variation and a relatively short period of functional capability in two-dimensional cultures, are not suitable for high-throughput screening procedures...
July 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29786560/microfabrication-of-liver-and-heart-tissues-for-drug-development
#4
REVIEW
Grace E Brown, Salman R Khetani
Drug-induced liver- and cardiotoxicity remain among the leading causes of preclinical and clinical drug attrition, marketplace drug withdrawals and black-box warnings on marketed drugs. Unfortunately, animal testing has proven to be insufficient for accurately predicting drug-induced liver- and cardiotoxicity across many drug classes, likely due to significant differences in tissue functions across species. Thus, the field of in vitro human tissue engineering has gained increasing importance over the last 10 years...
July 5, 2018: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/29786430/galaxygpcrloop-template-based-and-ab-initio-structure-sampling-of-the-extracellular-loops-of-g-protein-coupled-receptors
#5
Jonghun Won, Gyu Rie Lee, Hahnbeom Park, Chaok Seok
The second extracellular loops (ECL2s) of G-protein-coupled receptors (GPCRs) are often involved in GPCR functions, and their structures have important implications in drug discovery. However, structure prediction of ECL2 is difficult because of its long length and the structural diversity among different GPCRs. In this study, a new ECL2 conformational sampling method involving both template-based and ab initio sampling was developed. Inspired by observation of similar ECL2 structures of closely related GPCRs, a template-based sampling method employing loop structure templates selected from the structure database was developed...
May 22, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29785561/reptb-a-gene-ontology-based-drug-repurposing-approach-for-tuberculosis
#6
Anurag Passi, Neeraj Kumar Rajput, David J Wild, Anshu Bhardwaj
Tuberculosis (TB) is the world's leading infectious killer with 1.8 million deaths in 2015 as reported by WHO. It is therefore imperative that alternate routes of identification of novel anti-TB compounds are explored given the time and costs involved in new drug discovery process. Towards this, we have developed RepTB. This is a unique drug repurposing approach for TB that uses molecular function correlations among known drug-target pairs to predict novel drug-target interactions. In this study, we have created a Gene Ontology based network containing 26,404 edges, 6630 drug and 4083 target nodes...
May 21, 2018: Journal of Cheminformatics
https://www.readbyqxmd.com/read/29785480/potential-treatment-options-in-a-post-antibiotic-era
#7
R R Bragg, C M Meyburgh, J-Y Lee, M Coetzee
Following the Golden Age of antibiotic discovery in the previous century, the rate of antibiotic discovery has plummeted during the past 50 years while the incidence of antimicrobial resistance is ever-increasing. Presently, humankind is forced to address a major public health threat in the form of multiple drug resistance and urgent action is required to halt the advent of a post-antibiotic era. This chapter aims to draw the attention to the escalating global crisis of antimicrobial resistance fueled by the irresponsible use of antibiotics in healthcare and animal production sectors...
2018: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/29785244/more-than-just-an-immunosuppressant-the-emerging-role-of-fty720-as-a-novel-inducer-of-ros-and-apoptosis
#8
REVIEW
Teruaki Takasaki, Kanako Hagihara, Ryosuke Satoh, Reiko Sugiura
Fingolimod hydrochloride (FTY720) is a first-in-class of sphingosine-1-phosphate (S1P) receptor modulator approved to treat multiple sclerosis by its phosphorylated form (FTY720-P). Recently, a novel role of FTY720 as a potential anticancer drug has emerged. One of the anticancer mechanisms of FTY720 involves the induction of reactive oxygen species (ROS) and subsequent apoptosis, which is largely independent of its property as an S1P modulator. ROS have been considered as a double-edged sword in tumor initiation/progression...
2018: Oxidative Medicine and Cellular Longevity
https://www.readbyqxmd.com/read/29785193/gallnuts-a-potential-treasure-in-anticancer-drug-discovery
#9
REVIEW
Jiayu Gao, Xiao Yang, Weiping Yin, Ming Li
Introduction. In the discovery of more potent and selective anticancer drugs, the research continually expands and explores new bioactive metabolites coming from different natural sources. Gallnuts are a group of very special natural products formed through parasitic interaction between plants and insects. Though it has been traditionally used as a source of drugs for the treatment of cancerous diseases in traditional and folk medicinal systems through centuries, the anticancer properties of gallnuts are barely systematically reviewed...
2018: Evidence-based Complementary and Alternative Medicine: ECAM
https://www.readbyqxmd.com/read/29784669/autophagy-cell-viability-and-chemo-resistance-are-regulated-by-mir-489-in-breast-cancer
#10
Hexin Chen, Mithil Soni, Yogin Patel, Eleni Markoutsa, Chunfa Jie, Shou Liu, Peisheng Xu
It is postulated that the complexity and heterogeneity in cancer may hinder most efforts that target a single pathway. Thus, discovery of novel therapeutic agents targeting multiple pathways, such as microRNAs (miRs), holds promise for future cancer therapy. One such miR, miR-489, is downregulated in majority of breast cancer cells and several drug-resistant breast cancer cell lines, but its role and underlying mechanism for tumor suppression and drug resistance needs further investigation. The current study identifies autophagy as a novel pathway targeted by miR-489 and reports Unc-51 like autophagy activating kinase 1 (ULK1) and lysosomal protein transmembrane 4 beta (LAPTM4B) to be direct targets of miR-489...
May 21, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29784364/protein-binding-protection-in-combination-with-dna-masking-for-sensitive-and-reliable-transcription-factor-detection
#11
Xiaowen Xu, Lei Wang, Desong Zhu, Yan Wang, Wei Jiang
Sensitive and reliable detection of transcription factors (TFs) is crucial for disease diagnosis and drug discovery. Herein, a protein binding protection in combination with DNA masking-based strategy is developed for sensitive and reliable detection of NF-κB p50. First, NF-κB p50 binds specifically to a hairpin probe to form a protein-DNA complex. Then, the formed complex protects the hairpin probe from hybridization with the masking strand and subsequently triggers the cascade signal amplification of strand displacement amplification (SDA) and exponential rolling circle amplification (ERCA)...
August 15, 2018: Talanta
https://www.readbyqxmd.com/read/29784049/identification-and-therapeutic-modulation-of-a-pro-inflammatory-subset-of-disease-associated-microglia-in-alzheimer-s-disease
#12
Srikant Rangaraju, Eric B Dammer, Syed Ali Raza, Priyadharshini Rathakrishnan, Hailian Xiao, Tianwen Gao, Duc M Duong, Michael W Pennington, James J Lah, Nicholas T Seyfried, Allan I Levey
BACKGROUND: Disease-associated-microglia (DAM) represent transcriptionally-distinct and neurodegeneration-specific microglial profiles with unclear significance in Alzheimer's disease (AD). An understanding of heterogeneity within DAM and their key regulators may guide pre-clinical experimentation and drug discovery. METHODS: Weighted co-expression network analysis (WGCNA) was applied to existing microglial transcriptomic datasets from neuroinflammatory and neurodegenerative disease mouse models to identify modules of highly co-expressed genes...
May 21, 2018: Molecular Neurodegeneration
https://www.readbyqxmd.com/read/29783926/neural-networks-for-link-prediction-in-realistic-biomedical-graphs-a-multi-dimensional-evaluation-of-graph-embedding-based-approaches
#13
Gamal Crichton, Yufan Guo, Sampo Pyysalo, Anna Korhonen
BACKGROUND: Link prediction in biomedical graphs has several important applications including predicting Drug-Target Interactions (DTI), Protein-Protein Interaction (PPI) prediction and Literature-Based Discovery (LBD). It can be done using a classifier to output the probability of link formation between nodes. Recently several works have used neural networks to create node representations which allow rich inputs to neural classifiers. Preliminary works were done on this and report promising results...
May 21, 2018: BMC Bioinformatics
https://www.readbyqxmd.com/read/29783865/flow-cytometry-based-epitope-binning-using-competitive-binding-profiles-for-the-characterization-of-monoclonal-antibodies-against-cellular-and-soluble-protein-targets
#14
Brian M Chan, Anita Badh, Kelly A Berry, Stephanie A Grauer, Chadwick T King
A key step in the therapeutic antibody drug discovery process is early identification of diverse candidate molecules. Information comparing antibody binding epitopes can be used to classify antibodies within a large panel, guiding rational lead molecule selection. We describe a novel epitope binning method utilizing high-throughput flow cytometry (HTFC) that leverages cellular barcoding or spectrally distinct beads to multiplex samples to characterize antibodies raised against cell membrane receptor or soluble protein targets...
May 1, 2018: SLAS Discovery
https://www.readbyqxmd.com/read/29783691/old-and-young-actors-playing-novel-roles-in-the-drama-of-multiple-myeloma-bone-marrow-microenvironment-dependent-drug-resistance
#15
REVIEW
Sabrina Manni, Marilena Carrino, Gianpietro Semenzato, Francesco Piazza
Multiple myeloma (MM) is the second most frequent hematologic cancer. In addition to the deleterious effects of neoplastic plasma cell growth and spreading during the disease evolution, this tumor is characterized by the serious pathological consequences due to the massive secretion of monoclonal immunoglobulins and by the derangement of bone physiology with progressive weakening of the skeleton. Despite significant progresses having been made in the last two decades in the therapeutic management of this plasma cell tumor, MM remains invariably lethal, due to its extremely complex genetic architecture and to the constant protection it receives from the tumor niche, which is represented by the bone marrow microenvironment...
May 18, 2018: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/29783192/interaction-of-dna-and-mononucleotides-with-theophylline-investigated-using-electrochemical-biosensors-and-biosensing
#16
Katarína Nemčeková, Ján Labuda, Viktor Milata, Jana Blaškovičová, Jozef Sochr
The understanding of DNA-drug interaction mechanism is among the important aspects of biological studies for drug design, discovery and pharmaceutical development processes. Published rather detailed FTIR and UV-visible spectroscopic studies on the interactions of theophylline, theobromine and caffeine with calf thymus DNA have shown effective binding of these methylxanthine derivatives to DNA and RNA involving H-bonds. However, to our knowledge, there is no such investigation using electrochemical approach...
May 3, 2018: Bioelectrochemistry
https://www.readbyqxmd.com/read/29782894/screening-of-the-mmv-and-gsk-open-access-chemical-boxes-using-a-viability-assay-developed-against-the-kinetoplastid-crithidia-fasciculata
#17
Wakisa Kipandula, Simon A Young, Stuart A MacNeill, Terry K Smith
Diseases caused by the pathogenic kinetoplastids continue to incapacitate and kill hundreds of thousands of people annually throughout the tropics and sub-tropics. Unfortunately, in the countries where these neglected diseases occur, financial obstacles to drug discovery and technical limitations associated with biochemical studies impede the development of new, safe, easy to administer and effective drugs. Here we report the development and optimisation of a Crithidia fasciculata resazurin viability assay, which is subsequently used for screening and identification of anti-crithidial compounds in the MMV and GSK open access chemical boxes...
May 18, 2018: Molecular and Biochemical Parasitology
https://www.readbyqxmd.com/read/29782889/development-of-robust-genotype-1a-hepatitis-c-replicons-harboring-adaptive-mutations-for-facilitating-the-antiviral-drug-discovery-and-study-of-virus-replication
#18
Hui-Mei Lin, Pei-Shan Wu, Han-Shu Hu, Wan-Chun Chang, Ren-Huang Wu, Jia-Ni Tian, Jyh-Haur Chern, Andrew Yueh
The hepatitis C virus (HCV) subgenomic replicon is a valuable tool for studying virus replication and HCV drug development. Despite the fact that HCV genotype 1a (HCV1a) is the most prevalent genotype in the United States, few HCV1a reporter replicon constructs have been reported, and their replication capacities are not as efficient as those of HCV1b or 2a, especially in transient expression. In this study, we selected efficient HCV1a replicons and characterized the novel adaptive mutations derived from stable HCV1a (strain H77) replicon cells after G418 selection...
May 18, 2018: Journal of Virological Methods
https://www.readbyqxmd.com/read/29782872/oxyfadichalcone-c-inhibits-melanoma-a375-cell-proliferation-and-metastasis-via-suppressing-pi3k-akt-and-mapk-erk-pathways
#19
Xiaolin Peng, Zhengming Wang, Yang Liu, Xin Peng, Yao Liu, Shan Zhu, Zhe Zhang, Yuling Qiu, Meihua Jin, Ran Wang, Qingying Zhang, Dexin Kong
AIMS: Melanoma remains to be one of the most incurable cancers. Discovery of novel antitumor agent for melanoma therapy is expected. We recently isolated Oxyfadichalcone C from Oxytropis falcate and investigated the anti-proliferative and anti-metastatic activity on human melanoma A375 cells in vitro. MAIN METHODS: Cell viability was determined using MTT assay and soft agar cloning formation assay. The effect of Oxyfadichalcone C on cell cycle distribution and apoptosis were analyzed by flow cytometry...
May 18, 2018: Life Sciences
https://www.readbyqxmd.com/read/29782488/insight-into-small-molecule-binding-to-the-neonatal-fc-receptor-by-x-ray-crystallography-and-100-khz-magic-angle-spinning-nmr
#20
Daniel Stöppler, Alex Macpherson, Susanne Smith-Penzel, Nicolas Basse, Fabien Lecomte, Hervé Deboves, Richard D Taylor, Tim Norman, John Porter, Lorna C Waters, Marta Westwood, Ben Cossins, Katharine Cain, James White, Robert Griffin, Christine Prosser, Sebastian Kelm, Amy H Sullivan, David Fox, Mark D Carr, Alistair Henry, Richard Taylor, Beat H Meier, Hartmut Oschkinat, Alastair D Lawson
Aiming at the design of an allosteric modulator of the neonatal Fc receptor (FcRn)-Immunoglobulin G (IgG) interaction, we developed a new methodology including NMR fragment screening, X-ray crystallography, and magic-angle-spinning (MAS) NMR at 100 kHz after sedimentation, exploiting very fast spinning of the nondeuterated soluble 42 kDa receptor construct to obtain resolved proton-detected 2D and 3D NMR spectra. FcRn plays a crucial role in regulation of IgG and serum albumin catabolism. It is a clinically validated drug target for the treatment of autoimmune diseases caused by pathogenic antibodies via the inhibition of its interaction with IgG...
May 21, 2018: PLoS Biology
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