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https://www.readbyqxmd.com/read/28922808/the-discovery-of-ceftazidime-avibactam-as-an-anti-mycobacterium-avium-agent
#1
Devyani Deshpande, Shashikant Srivastava, Moti L Chapagain, Pooi S Lee, Kayle N Cirrincione, Jotam G Pasipanodya, Tawanda Gumbo
Objectives: To determine if ceftaroline and ceftazidime combined with avibactam are efficacious against pulmonary Mycobacterium avium complex (MAC) disease. Methods: First, we performed a concentration-effect study of ceftaroline and ceftaroline/avibactam against extracellular MAC in test tubes. Given the difficulty of obtaining avibactam at the time of experimentation, we used a single concentration of commercial ceftazidime/avibactam, and two sets of non-treated controls, one with ceftazidime/avibactam and the other without...
September 1, 2017: Journal of Antimicrobial Chemotherapy
https://www.readbyqxmd.com/read/28922589/higher-baseline-proinflammatory-cytokines-mark-poor-antidepressant-response-in-bipolar-disorder
#2
Francesco Benedetti, Sara Poletti, Thomas A Hoogenboezem, Clara Locatelli, Harm de Wit, Annemarie J M Wijkhuijs, Cristina Colombo, Hemmo A Drexhage
BACKGROUND: The clinical relevance of raised levels of circulating cytokines in bipolar disorder is still unclear. Cytokines influence neurotransmitters, neuroplasticity, and white matter integrity. An inconsistent literature suggests that higher cytokine levels could hamper antidepressant response. Total sleep deprivation (TSD) and light therapy (LT) prompt a rapid antidepressant response and can provide a model treatment to study predictors of response. METHODS: We studied at baseline 15 immune-regulating compounds in 37 consecutively admitted inpatients with a major depressive episode in the course of bipolar disorder (DSM-5 criteria) and in 24 controls...
September 12, 2017: Journal of Clinical Psychiatry
https://www.readbyqxmd.com/read/28922023/fatty-acid-synthase-fasn-as-a-therapeutic-target-in-breast-cancer
#3
Javier A Menendez, Ruth Lupu
Ten years ago, we put forward the metabolo-oncogenic nature of fatty acid synthase (FASN) in breast cancer. Since the conception of this hypothesis, which provided a model to explain how FASN is intertwined with various signaling networks to cell-autonomously regulate breast cancer initiation and progression, FASN has received considerable attention as a therapeutic target. However, despite the ever-growing evidence demonstrating the involvement of FASN as part of the cancer-associated metabolic reprogramming, translation of the basic science-discovery aspects of FASN blockade to the clinical arena remains a challenge...
September 18, 2017: Expert Opinion on Therapeutic Targets
https://www.readbyqxmd.com/read/28921648/rna-therapeutics-in-oncology-advances-challenges-and-future-directions
#4
A Robert MacLeod, Stanley T Crooke
RNA-based therapeutic technologies represent a rapidly expanding class of therapeutic opportunities with the power to modulate cellular biology in ways never before possible. With RNA-targeted therapeutics, inhibitors of previously undruggable proteins, gene expression modulators, and even therapeutic proteins can be rationally designed based on sequence information alone, something that is not possible with other therapeutic modalities. The most advanced RNA therapeutic modalities are antisense oligonucleotides (ASOs) and small interfering RNAs...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28921644/clinical-pharmacology-considerations-for-the-development-of-immune-checkpoint-inhibitors
#5
Jennifer Sheng, Shivani Srivastava, Kinjal Sanghavi, Zheng Lu, Brian J Schmidt, Akintunde Bello, Manish Gupta
Immuno-oncology works through activation of the patient's immune system against cancer, with several advantages over other treatment approaches, including cytotoxic agents and molecular-targeted therapies. The most notable feature of immuno-oncology treatments is the nature of the patient responses achieved, which can be more durable and sustained than with other modalities. Increased understanding of immune system complexity has provided a number of opportunities to advance several strategies for the development of immuno-oncology therapies...
October 2017: Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/28920461/discovery-and-development-of-tramadol-for-the-treatment-of-pain
#6
Lidia Bravo, Juan Antonio Mico, Esther Berrocoso
Tramadol is an opioid drug that, unlike classic opioids, also modulates the monoaminergic system by inhibiting noradrenergic and serotoninergic reuptake. For this reason, tramadol is considered an atypical opioid. These special pharmacological characteristics have made tramadol one of the most commonly prescribed analgesic drugs to treat moderate to severe pain. Areas covered: The aim of this review is to provide a historical description of the biochemistry, pharmacokinetics and particularly, the mechanisms of action of tramadol...
September 17, 2017: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/28920432/plk1-targeted-fluorescent-tumor-imaging-with-high-signal-background-ratio
#7
Ji-Ting Hou, Kyung-Phil Ko, Hu Shi, Wen Xiu Ren, Peter Verwilst, Seyoung Koo, Jin Yong Lee, Sung-Gil Chi, Jong Seung Kim
As significantly expressed during cell division, polo-like kinase 1 (PLK1) plays crucial roles in numerous mitotic events and has attracted interest as a potential therapeutic marker in oncological drug discovery. We prepared two small molecular fluorescent probes, 1 and 2, conjugated to SBE13 (a type II PLK1 inhibitor) to investigate the PLK1-targeted imaging of cancer cells and tumors. Enzymatic docking studies, molecular dynamics simulations, in vitro and in vivo imaging experiments, all supported the selective targeting and visualization of PLK1 expressing cells by probes 1 and 2, and probe 2 was successfully demonstrated to image PLK1-upregualted tumors with a remarkable signal to background ratios...
September 18, 2017: ACS Sensors
https://www.readbyqxmd.com/read/28919906/screening-for-natural-inhibitors-of-topoisomerases-i-from-rhamnus-davurica-by-affinity-ultrafiltration-and-high-performance-liquid-chromatography-mass-spectrometry
#8
Guilin Chen, Mingquan Guo
Topoisomerase I (Topo I) catalyzes topological interconversion of duplex DNA during DNA replication and transcription, and has been deemed as important antineoplastic targets. In this study, the fraction R.d-60 from ethyl acetate extracts of Rhamnus davurica showed higher inhibitory rates against SGC-7901 and HT-29 compared with the R.d-30 fraction in vitro. However, the specific active components of R.d-60 fraction remain elusive. To this end, a method based on bio-affinity ultrafiltration and high performance liquid chromatography/electrospray mass spectrometry (HPLC- ESI-MS/MS) was developed to rapidly screen and identify the Topo I inhibitors in this fraction...
2017: Frontiers in Plant Science
https://www.readbyqxmd.com/read/28919707/quantum-mechanics-implementation-in-drug-design-workflows-does-it-really-help
#9
REVIEW
Olayide A Arodola, Mahmoud Es Soliman
The pharmaceutical industry is progressively operating in an era where development costs are constantly under pressure, higher percentages of drugs are demanded, and the drug-discovery process is a trial-and-error run. The profit that flows in with the discovery of new drugs has always been the motivation for the industry to keep up the pace and keep abreast with the endless demand for medicines. The process of finding a molecule that binds to the target protein using in silico tools has made computational chemistry a valuable tool in drug discovery in both academic research and pharmaceutical industry...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28919409/solasodine-3-o-%C3%AE-d-glucopyranoside-is-hydrolyzed-by-a-membrane-glucosidase-into-active-molecule-solasodine-against-candida-albicans
#10
Wenqiang Chang, Ying Li, Sha Zheng, Ming Zhang, Yanhui Gao, Hongxiang Lou
Antifungal activity of some natural molecules can be abated or blocked by efflux pumps in Candida albicans, which restricts the discovery of potential antifungal agents. Here we found that the steroidal alkaloid solasodine is active against C. albicans efflux pump-deficient strains but inert towards the wild type. However, the glucosylated solasodine-3-O-β-D-glucopyranoside exhibits antifungal activity towards the wild type strain. Further investigation revealed that the entry of solasodine into C. albicans cells is blocked by efflux pumps...
September 15, 2017: Food and Chemical Toxicology
https://www.readbyqxmd.com/read/28919180/development-of-a-cyclosporin-a-derivative-with-excellent-anti-hepatitis-c-virus-potency
#11
Jiping Fu, Christopher Becker, Li Cao, Michael Capparelli, Regis Denay, Roger Fujimoto, Yu Gai, Zhaobo Gao, Christian Guenat, Subramanian Karur, Hongyong Kim, Weikuan Li, Xiaolin Li, Wei Li, Thomas Lochmann, Amy Lu, Peichao Lu, Alexandre Luneau, Nicole Meier, Wosenu Mergo, Simon Ng, David Parker, Yunshan Peng, Bernard Riss, Alexey Rivkin, Silvio Roggo, Harald Schroeder, Friedrich Schuerch, Robert L Simmons, Feng Sun, Zachary K Sweeney, Meiliana Tjandra, Michael Wang, Ruidong Wang, Andrew H Weiss, Nicolas Wenger, Quanbing Wu, Xin Xiong, Su Xu, Wenjian Xu, Aregahegn Yifru, Jibin Zhao, Jianguang Zhou, Christian Zürcher, Fabrice Gallou
Synthetic modification of cyclosporin A at P3-P4 positions led to the discovery of NIM258, a next generation cyclophilin inhibitor with excellent anti-hepatitis C virus potency, with decreased transporter inhibition, and pharmacokinetics suitable for coadministration with other drugs. Herein is disclosed the evolution of the synthetic strategy to from the original medicinal chemistry route, designed for late diversification, to a convergent and robust development synthesis. The chiral centers in the P4 fragment were constructed by an asymmetric chelated Claisen rearrangement in the presence of quinidine as the chiral ligand...
September 7, 2017: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28919040/heme-binding-biguanides-target-cytochrome-p450-dependent-cancer-cell-mitochondria
#12
Zhijun Guo, Irina F Sevrioukova, Ilia G Denisov, Xia Zhang, Ting-Lan Chiu, Dafydd G Thomas, Eric A Hanse, Rebecca A D Cuellar, Yelena V Grinkova, Vanessa Wankhede Langenfeld, Daniel S Swedien, Justin D Stamschror, Juan Alvarez, Fernando Luna, Adela Galván, Young Kyung Bae, Julia D Wulfkuhle, Rosa I Gallagher, Emanuel F Petricoin, Beverly Norris, Craig M Flory, Robert J Schumacher, M Gerard O'Sullivan, Qing Cao, Haitao Chu, John D Lipscomb, William M Atkins, Kalpna Gupta, Ameeta Kelekar, Ian A Blair, Jorge H Capdevila, John R Falck, Stephen G Sligar, Thomas L Poulos, Gunda I Georg, Elizabeth Ambrose, David A Potter
The mechanisms by which cancer cell-intrinsic CYP monooxygenases promote tumor progression are largely unknown. CYP3A4 was unexpectedly associated with breast cancer mitochondria and synthesized arachidonic acid (AA)-derived epoxyeicosatrienoic acids (EETs), which promoted the electron transport chain/respiration and inhibited AMPKα. CYP3A4 knockdown activated AMPKα, promoted autophagy, and prevented mammary tumor formation. The diabetes drug metformin inhibited CYP3A4-mediated EET biosynthesis and depleted cancer cell-intrinsic EETs...
August 29, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28919038/covalent-ligand-discovery-against-druggable-hotspots-targeted-by-anti-cancer-natural-products
#13
Elizabeth A Grossman, Carl C Ward, Jessica N Spradlin, Leslie A Bateman, Tucker R Huffman, David K Miyamoto, Jordan I Kleinman, Daniel K Nomura
Many natural products that show therapeutic activities are often difficult to synthesize or isolate and have unknown targets, hindering their development as drugs. Identifying druggable hotspots targeted by covalently acting anti-cancer natural products can enable pharmacological interrogation of these sites with more synthetically tractable compounds. Here, we used chemoproteomic platforms to discover that the anti-cancer natural product withaferin A targets C377 on the regulatory subunit PPP2R1A of the tumor-suppressor protein phosphatase 2A (PP2A) complex leading to activation of PP2A activity, inactivation of AKT, and impaired breast cancer cell proliferation...
September 11, 2017: Cell Chemical Biology
https://www.readbyqxmd.com/read/28918974/pigmentary-changes-in-patients-treated-with-targeted-anticancer-agents-a-systematic-review-and-meta-analysis
#14
Julia Dai, Viswanath R Belum, Shenhong Wu, Vincent Sibaud, Mario E Lacouture
BACKGROUND: The discovery of signaling networks that drive oncogenic processes has led to the development of targeted anticancer agents. The burden of pigmentary adverse events from these drugs is unknown. OBJECTIVE: To conduct a systematic review and meta-analysis of published clinical trials and determine the incidence and risk of development of targeted therapy-induced pigmentary changes. METHODS: A comprehensive search was conducted to identify studies reporting targeted therapy-induced pigmentary changes...
September 14, 2017: Journal of the American Academy of Dermatology
https://www.readbyqxmd.com/read/28918329/an-integrated-strategy-for-rapid-discovery-and-identification-of-the-sequential-piperine-metabolites-in-rats-using-ultra-high-performance-liquid-chromatography-high-resolution-mass-spectrometery
#15
Zhanpeng Shang, Wei Cai, Yanfeng Cao, Fei Wang, Zhibin Wang, Jianqiu Lu, Jiayu Zhang
Piperine, one of the major bioactive constituents isolated from natural flavorings and medicinal-culinary herbs, possesses various biological activities. In the present study, an integrated strategy based on ultra high-performance liquid chromatography/high resolution mass spectrometry was established to reveal piperine metabolism in rats. First of all, post-acquisition data-mining methods, including high resolution extracted ion chromatograms (HREICs) and multiple mass defect filtering (MMDF), were used to screen piperine metabolite candidates in a full-scan HRMS(1) level...
September 9, 2017: Journal of Pharmaceutical and Biomedical Analysis
https://www.readbyqxmd.com/read/28918320/in-silico-interaction-analysis-of-cannabinoid-receptor-interacting-protein-1b-crip1b-cb1-cannabinoid-receptor
#16
Pratishtha Singh, Anjali Ganjiwale, Allyn C Howlett, Sudha M Cowsik
Cannabinoid Receptor Interacting Protein isoform 1b (CRIP1b) is known to interact with the CB1 receptor. Alternative splicing of the CNRIP1 gene produces CRIP1a and CRIP1b with a difference in the third exon only. Exons 1 and 2 encode for a functional domain in both proteins. CRIP1a is involved in regulating CB1 receptor internalization, but the function of CRIP1b is not very well characterized. Since there are significant identities in functional domains of these proteins, CRIP1b is a potential target for drug discovery...
September 6, 2017: Journal of Molecular Graphics & Modelling
https://www.readbyqxmd.com/read/28918096/a-comprehensive-review-on-aurora-kinase-small-molecule-inhibitors-and-clinical-trial-studies
#17
REVIEW
Ankit C Borisa, Hardik G Bhatt
Aurora kinase belongs to serine/threonine kinase family which controls cell division. Therapeutic inhibition of Aurora kinase showed great promise as probable anticancer regime because of its important role during cell division. Here, in this review, we have carried out exhaustive study of various synthetic molecules reported as Aurora kinase inhibitors and developed as lead molecule at various stages of clinical trials from its discovery in 1995 to till date. We reported details of small molecules, specifically inhibiting all 3 types of Aurora kinases, which includes extensive literature search in various database like various scientific journals, patents, scifinder and PubMed database, internet resources, books, etc...
August 24, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28917974/cross-cultural-analysis-of-medicinal-plants-commonly-used-in-ethnoveterinary-practices-at-south-waziristan-agency-and-bajaur-agency-federally-administrated-tribal-areas-fata-pakistan
#18
Muhammad Abdul Aziz, Muhammad Adnan, Amir Hasan Khan, Muhammad Sufyan, Shahid Niaz Khan
ETHNOPHARMACOLOGICAL RELEVANCE: In remote areas, medicinal plants have an imperative role in curing various livestock's ailments. In Pakistan, people residing in remote areas including South Waziristan Agency and Bajaur Agency depend on traditional herbal remedies for treating their domestic animals. Medicinal plants are an important part of the medical system in these Agencies. The prime goal of the current study is to explore the ethnoveterinary practices in the two regions and discuss cross-cultural consensus on the use of medicinal plants...
September 13, 2017: Journal of Ethnopharmacology
https://www.readbyqxmd.com/read/28917785/fluorescence-quenching-based-alkaline-phosphatase-activity-detection
#19
Yaqi Mei, Qiong Hu, Baojing Zhou, Yonghui Zhang, Minhui He, Ting Xu, Feng Li, Jinming Kong
Simple and fast detection of alkaline phosphatase (ALP) activity is of great importance for diagnostic and analytical applications. In this work, we report a turn-off approach for the real-time detection of ALP activity on the basis of the charge transfer induced fluorescence quenching of the Cu(BCDS)2(2-) (BCDS = bathocuproine disulfonate) probe. Initially, ALP can enzymatically hydrolyze the substrate ascorbic acid 2-phosphate to release ascorbic acid (AA). Subsequently, the AA-mediated reduction of the Cu(BCDS)2(2-) probe, which displays an intense photoluminescence band at the wavelength of 402nm, leads to the static quenching of fluorescence of the probe as a result of charge transfer...
January 1, 2018: Talanta
https://www.readbyqxmd.com/read/28917711/crocodiles-and-alligators-antiamoebic-and-antitumor-compounds-of-crocodiles
#20
Ruqaiyyah Siddiqui, Shareni Jeyamogan, Salwa Mansoor Ali, Fatima Abbas, K A Sagathevan, Naveed Ahmed Khan
Crocodiles exist in unsanitary environments, feed on rotten meat, are often exposed to heavy metals such as arsenic, cadmium, cobalt, chromium, mercury, nickel, lead, selenium, tolerate high levels of radiation, and are amid the very few species to survive the catastrophic Cretaceous-Tertiary extinction event, nonetheless they can live for up to a 100 years. Moreover, as they live in unhygienic conditions, they regularly come across pathogens. Logically, we postulate that crocodiles have established mechanisms to defend themselves from noxious agents as well as protecting themselves from pathogens...
September 13, 2017: Experimental Parasitology
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