128,469 results match your criteria drug discovery


A key review on oxadiazole analogs as potential methicillin-resistant Staphylococcus aureus (MRSA) activity: Structure-activity relationship studies.

Eur J Med Chem 2021 Apr 17;219:113442. Epub 2021 Apr 17.

Department of Studies in Chemistry, Manasagangotri, University of Mysore, Mysuru, 570006, India. Electronic address:

Methicillin-resistant Staphylococcus aureus (MRSA) is becoming dangerous to human beings due to easy transmission mode and leading to the difficult-to-treat situation. The rapid resistance development of MRSA to many approved antibiotics is of major concern. There is a lot of scope to develop novel, efficient, specific, and nontoxic drug candidates to fight against MRSA isolates. Read More

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KenDTI: an ensemble model based on network integration and CNN for drug-target interaction prediction.

IEEE/ACM Trans Comput Biol Bioinform 2021 Apr 20;PP. Epub 2021 Apr 20.

The identification of drug-target interactions (DTIs) is an essential step in the process of drug discovery. As experimental validation suffers from high cost and low success rate, various computational models have been exploited to infer potential DTIs. The performance of DTI prediction depends heavily on the features extracted from drugs and target proteins. Read More

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ASSAY and Drug Development Technologies.

Authors:
Bruce Melancon

Assay Drug Dev Technol 2021 Apr 20. Epub 2021 Apr 20.

Vanderbilt Center for Neuroscience Drug Discovery, Franklin, TN, USA.

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Betulonic Acid Derivatives Interfering with Human Coronavirus 229E Replication via the nsp15 Endoribonuclease.

J Med Chem 2021 Apr 20. Epub 2021 Apr 20.

Laboratory of Virology and Chemotherapy, Rega Institute, KU Leuven, 3000 Leuven, Belgium.

To develop antiviral therapeutics against human coronavirus (HCoV) infections, suitable coronavirus drug targets and corresponding lead molecules must be urgently identified. Here, we describe the discovery of a class of HCoV inhibitors acting on nsp15, a hexameric protein component of the viral replication-transcription complexes, endowed with immune evasion-associated endoribonuclease activity. Structure-activity relationship exploration of these 1,2,3-triazolo-fused betulonic acid derivatives yielded lead molecule as a strong inhibitor (antiviral EC: 0. Read More

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Ten-Year Retrospective of the Vanderbilt Institute of Chemical Biology Chemical Synthesis Core.

ACS Chem Biol 2021 Apr 20. Epub 2021 Apr 20.

Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States.

Chemical synthesis has been described as a central science. Its practice provides access to the chemical structures of known and/or designed function. In particular, human health is greatly impacted by synthesis that enables advancements in both basic science discoveries in chemical biology as well as translational research that can lead to new therapeutics. Read More

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Studying RNA-Protein Complexes Using X-Ray Crystallography.

Methods Mol Biol 2021 ;2263:423-446

Advanced Drug Delivery, Pharmaceutical Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

A wide range of biological processes rely on complexes between ribonucleic acids (RNAs) and proteins. Determining the three-dimensional structures of RNA-protein complexes is crucial to elucidate the relationship between structure and biological function. X-ray crystallography represents the most widely used technique to characterize RNA-protein complexes at atomic resolution; however, determining their three-dimensional structures remains challenging. Read More

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January 2021

Fragment Screening by NMR.

Authors:
Ben J Davis

Methods Mol Biol 2021 ;2263:247-270

Vernalis Research, Cambridge, UK.

This chapter describes the use of NMR to screen a fragment library as part of a fragment-based lead discovery (FBLD) campaign. The emphasis is on the practicalities involved in fragment screening by NMR, with particular attention to the use of 1D ligand-observed H NMR experiments. An overview of the theoretical considerations underlying the choice of method and experimental configuration is given, along with a discussion of steps that can be taken in order to minimize the risk of experimental artifacts often associated with the identification of low-affinity interactions. Read More

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January 2021

Ligand Discovery: High-Throughput Binding: Fluorescence Polarization (Anisotropy).

Methods Mol Biol 2021 ;2263:231-246

AstraZeneca R&D Discovery Sciences, Cambridge, UK.

High-throughput assays based on fluorescence polarization (or fluorescence anisotropy) technology have often been employed for primary hit-finding in drug discovery. These binding assays provide a homogeneous format and consistent performance and offer advantages over some other optical methods. Developments in assay design and improvements in fluorescent probes have enabled the application of the technique to even complex biological systems. Read More

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January 2021

The Use of Acoustic Mist Ionization Mass Spectrometry for High-Throughput Screening.

Methods Mol Biol 2021 ;2263:217-230

Hit Discovery, Discovery Sciences, R&D BioPharmaceuticals, AstraZeneca, Alderley Park, UK.

It is clear from the analysis of the distribution of approved drug targets that enzymes continue to be a major target class for the pharmaceutical industry. The application of high-throughput screens designed to monitor the activity of these enzyme targets, and the ability of test compounds to modulate this activity, is still the predominant hit finding approach in the industry. The widespread use of enzyme activity-based screens has led to the development of several useful guidelines for the development and validation of robust and reliable assays. Read More

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January 2021

Expression Signatures of Cisplatin- and Trametinib-Treated Early-Stage Medaka Melanomas.

G3 (Bethesda) 2019 Jul;9(7):2267-2276

Physiological Chemistry, Biocenter, University of Wuerzburg, 97074 Wuerzburg, Germany.

Small aquarium fish models provide useful systems not only for a better understanding of the molecular basis of many human diseases, but also for first-line screening to identify new drug candidates. For testing new chemical substances, current strategies mostly rely on easy to perform and efficient embryonic screens. Cancer, however, is a disease that develops mainly during juvenile and adult stage. Read More

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A Call to Action for New Global Approaches to Cardiovascular Disease Drug Solutions.

Circulation 2021 Apr 20:CIR0000000000000981. Epub 2021 Apr 20.

Universite´ de Lorraine, INSERM CIC 1493, INI CRCT, CHRU, Nancy, France (F.Z.).

While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. Read More

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Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.

J Med Chem 2021 Apr 20. Epub 2021 Apr 20.

Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd, Dallas, Texas 75390-9135, United States.

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 () suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. Read More

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Architecture of the mycobacterial succinate dehydrogenase with a membrane-embedded Rieske FeS cluster.

Proc Natl Acad Sci U S A 2021 Apr;118(15)

State Key Laboratory of Medicinal Chemical Biology, Frontiers Science Center for Cell Responses, College of Life Sciences, Nankai University, Tianjin 300353, China;

Complex II, also known as succinate dehydrogenase (SQR) or fumarate reductase (QFR), is an enzyme involved in both the Krebs cycle and oxidative phosphorylation. Mycobacterial Sdh1 has recently been identified as a new class of respiratory complex II (type F) but with an unknown electron transfer mechanism. Here, using cryoelectron microscopy, we have determined the structure of Sdh1 in the presence and absence of the substrate, ubiquinone-1, at 2. Read More

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Functional approaches to the study of G-protein-coupled receptors in postmortem brain tissue: [S]GTPγS binding assays combined with immunoprecipitation.

Pharmacol Rep 2021 Apr 20. Epub 2021 Apr 20.

Department of Pharmacology, Centro de Investigación Biomédica en Red de Salud Mental, University of the Basque Country UPV/EHU CIBERSAM, 48940, Leioa, Bizkaia, Spain.

G-protein-coupled receptors (GPCRs) have an enormous biochemical importance as they bind to diverse extracellular ligands and regulate a variety of physiological and pathological responses. G-protein activation measures the functional consequence of receptor occupancy at one of the earliest receptor-mediated events. Receptor coupling to G-proteins promotes the GDP/GTP exchange on Gα subunits. Read More

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A collagen glucosyltransferase drives lung adenocarcinoma progression in mice.

Commun Biol 2021 Apr 19;4(1):482. Epub 2021 Apr 19.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Cancer cells are a major source of enzymes that modify collagen to create a stiff, fibrotic tumor stroma. High collagen lysyl hydroxylase 2 (LH2) expression promotes metastasis and is correlated with shorter survival in lung adenocarcinoma (LUAD) and other tumor types. LH2 hydroxylates lysine (Lys) residues on fibrillar collagen's amino- and carboxy-terminal telopeptides to create stable collagen cross-links. Read More

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The cocaine and oxycodone biobanks, two repositories from genetically diverse and behaviorally characterized rats for the study of addiction.

eNeuro 2021 Apr 15. Epub 2021 Apr 15.

Department of Psychiatry, University of California, San Diego, La Jolla CA 92093, USA

Substance use disorders are pervasive in our society and have substantial personal and socio-economical costs. A critical hurdle in identifying biomarkers and novel targets for medication development is the lack of resources for obtaining biological samples with a detailed behavioral characterization of substance use disorder. Moreover, it is nearly impossible to find longitudinal samples. Read More

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Towards chemical validation of ribose 5-phosphate isomerase as a drug target.

Antimicrob Agents Chemother 2021 Apr 19. Epub 2021 Apr 19.

NovAliX, Biology Department, Illkirch Cedex, France

Neglected tropical diseases caused by kinetoplastid parasites (, and spp.) place a significant health and economic burden on developing nations worldwide. Current therapies are largely out-dated, inadequate and facing mounting drug resistance from the causative parasites. Read More

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Structural insights into the mechanisms of action of functionally distinct classes of Chikungunya virus nonstructural protein 1 inhibitors.

Antimicrob Agents Chemother 2021 Apr 19. Epub 2021 Apr 19.

Department of Medical Microbiology, Leiden University Medical Center, Leiden, the Netherlands

Chikungunya virus (CHIKV) nonstructural protein 1 (nsP1) harbours the methyltransferase (MTase) and guanylyltransferase (GTase) activities needed for viral RNA capping and represents a promising antiviral drug target. We compared the antiviral efficacy of nsP1 inhibitors belonging to the MADTP, CHVB and FHNA series [6'-fluoro-homoneplanocin A (FHNA), its 3'-keto form and 6'-β-Fluoro-homoaristeromycin]. Cell-based phenotypic cross-resistance assays revealed that the CHVB and MADTP series shared a similar mode of action that differed from that of the FHNA series. Read More

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Compound Sophorae Decoction: treating ulcerative colitis by affecting multiple metabolic pathways.

Chin J Nat Med 2021 Apr;19(4):267-283

Hubei Provincial Hospital of Traditional Chinese Medicine, Wuhan 430061, China; Hubei Province Academy of Traditional Chinese Medicine, Wuhan 430074, China. Electronic address:

Ulcerative colitis (UC) is a chronic refractory non-specific intestinal inflammatory disease that is difficult to be cured. The discovery of new ulcerative colitis-related metabolite biomarkers may help further understand UC and facilitate early diagnosis. It may also provide a basis for explaining the mechanism of drug action in the treatment of UC. Read More

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Pharmacological inhibition of nSMase2 reduces brain exosome release and α-synuclein pathology in a Parkinson's disease model.

Mol Brain 2021 Apr 19;14(1):70. Epub 2021 Apr 19.

Drug Discovery Lab, Department of Neurology, University of California, Los Angeles, CA, 90095, USA.

Aim: We have previously reported that cambinol (DDL-112), a known inhibitor of neutral sphingomyelinase-2 (nSMase2), suppressed extracellular vesicle (EV)/exosome production in vitro in a cell model and reduced tau seed propagation. The enzyme nSMase2 is involved in the production of exosomes carrying proteopathic seeds and could contribute to cell-to-cell transmission of pathological protein aggregates implicated in neurodegenerative diseases such as Parkinson's disease (PD). Here, we performed in vivo studies to determine if DDL-112 can reduce brain EV/exosome production and proteopathic alpha synuclein (αSyn) spread in a PD mouse model. Read More

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Frontiers of metal-coordinating drug design.

Expert Opin Drug Discov 2021 May 1;16(5):497-511. Epub 2020 Dec 1.

National Research Council (CNR) of Italy, Institute of Material (IOM) @ International School for Advanced Studies (SISSA), Trieste, Italy.

The occurrence of metal ions in biomolecules is required to exert vital cellular functions. Metal-containing biomolecules can be modulated by small-molecule inhibitors targeting their metal-moiety. As well, the discovery of cisplatin ushered the rational discovery of metal-containing-drugs. Read More

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Approaches for the discovery of new cell-penetrating peptides.

Expert Opin Drug Discov 2021 May 1;16(5):553-565. Epub 2020 Dec 1.

Department Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.

: The capability of cell-penetrating peptides (CPP), also known as protein transduction domains (PTD), to enter into cells possibly with an attached cargo, makes their application as delivery vectors or as direct therapeutics compelling. They are generally biocompatible, nontoxic, and easy to synthesize and modify. Three decades after the discovery of the first CPPs, ~2,000 CPP sequences have been identified, and many more predicted. Read More

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MedFused: A framework to discover the relationships between drug chemical functional group impacts and side effects.

Comput Biol Med 2021 Apr 11;133:104361. Epub 2021 Apr 11.

College of Science, Health and Engineering, La Trobe University, Melbourne, Australia. Electronic address:

It is a well-known fact that there are often side effects to the long-term use of certain medications. These side effects can vary from mild dizziness to, at its most serious, death. The main factors that cause these side effects are the chemical composition, the mode of treatment, and the dose. Read More

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Targeting Cul3-scaffold E3 ligase complex via KLHL substrate adaptors for cancer therapy.

Pharmacol Res 2021 Apr 16:105616. Epub 2021 Apr 16.

Institute of Pharmacology and Toxicology, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, 310058, China; Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, 310052, China; Cancer Center of Zhejiang University, Hangzhou, 310058, China. Electronic address:

Targeted therapy has become increasingly important and indispensable in cancer therapy. Cullin3-RING ligases (CRL3) serve as essential executors for regulating protein homeostasis in cancer development, highlighting that CRL3 might be promising targets in various cancer treatments. However, how to design new targeted therapies by disrupting the function of CRL3 are poorly understood. Read More

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Extracellular vesicles for tissue repair and regeneration: evidence, challenges and opportunities.

Adv Drug Deliv Rev 2021 Apr 16. Epub 2021 Apr 16.

Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden; Department of Materials, Imperial College London, London, UK; Department of Bioengineering, Imperial College London, London, UK; Institute of Biomedical Engineering, Imperial College London, London, UK. Electronic address:

Extracellular vesicles (EVs) are biological nanoparticles naturally secreted by cells, acting as delivery vehicles for molecular messages. During the last decade, EVs have been assigned multiple functions that have established their potential as therapeutic mediators for a variety of diseases and conditions. In this review paper, we report on the potential of EVs in tissue repair and regeneration. Read More

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Nimodipine inhibits intestinal and aortic smooth muscle contraction by regulating Ca-activated Cl channels.

Toxicol Appl Pharmacol 2021 Apr 16:115543. Epub 2021 Apr 16.

Liaoning Provincial Key Laboratory of Biotechnology and Drug Discovery, School of Life Sciences, Liaoning Normal University, Dalian 116000, PR China. Electronic address:

Nimodipine is a clinically used dihydropyridine L-type calcium channel antagonist that effectively inhibits transmembrane Ca influx following the depolarization of smooth muscle cells, but the detailed effect on smooth muscle contraction is not fully understood. Ca-activated Cl channels (CaCCs) in vascular smooth muscle cells (VSMCs) may regulate vascular contractility. We found that nimodipine can inhibit transmembrane protein 16A (TMEM16A) activity in a concentration-dependent manner by cell-based fluorescence-quenching assay and short-circuit current analysis, with an IC value of ~5 μM. Read More

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Targeting the NS2B-NS3 protease of tick-borne encephalitis virus with pan-flaviviral protease inhibitors.

Antiviral Res 2021 Apr 16:105074. Epub 2021 Apr 16.

Department of Medical Sciences, Clinical Microbiology, Uppsala University, Uppsala, Sweden. Electronic address:

Tick-borne encephalitis (TBE) is a severe neurological disorder caused by tick-borne encephalitis virus (TBEV), a member of the Flavivirus genus. Currently, two vaccines are available in Europe against TBEV. However, TBE cases have been rising in Sweden for the past twenty years, and thousands of cases are reported in Europe, emphasizing the need for antiviral treatments against this virus. Read More

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Pharmacology in the age of circuit neuroscience: Illuminating the neural mechanisms of reward, drug use and addiction and enlightening the future of translational research.

Pharmacol Biochem Behav 2021 Apr 16:173187. Epub 2021 Apr 16.

Addiction Biology Unit, Molecular Targets and Medications Discovery, Intramural Research Program, National Institute on Drug Abuse, Baltimore, MD 21224, USA.

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