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https://www.readbyqxmd.com/read/28538872/melanoma-tumor-microenvironment-and-new-treatments
#1
Mara Huffenbaecher Giavina-Bianchi, Pedro Francisco Giavina-Bianchi, Cyro Festa
In the recent past years, many discoveries in the tumor microenvironment have led to changes in the management of melanoma and it is rising up hopes, specially, to those in advanced stages. FDA approved seven new drugs from 2011 to 2014. They are: Vemurafenib, Dabrafenib and Trametinib, kinases inhibitors used for patients that have BRAFV600E mutation; Ipilimumab (anti-CTLA4), Pembrolizumab (anti-PD-1) and Nivolumab (anti-PD-1), monoclonal antibodies that stimulate the immune system; and Peginterferon alfa-2b, an anti-proliferative cytokine used as adjuvant therapy...
March 2017: Anais Brasileiros de Dermatologia
https://www.readbyqxmd.com/read/28538688/in-silico-study-and-bioprospection-of-the-antibacterial-and-antioxidant-effects-of-flavone-and-its-hydroxylated-derivatives
#2
Camila de Albuquerque Montenegro, Gregório Fernandes Gonçalves, Abrahão Alves de Oliveira Filho, Andressa Brito Lira, Thays Thyara Mendes Cassiano, Natanael Teles Ramos de Lima, José Maria Barbosa-Filho, Margareth de Fátima Formiga Melo Diniz, Hilzeth Luna Freire Pessôa
Flavonoid compounds are widely used as natural protective species, which can act as anti-inflammatory, antioxidant, anticoagulant, antihypertensive and antitumor agents. This study set out to investigate the probable pharmacological activities, along with the antibacterial and antioxidant effects, of flavone and its hydroxy derivatives: 3-hydroxyflavone, 5-hydroxyflavone and 6-hydroxyflavone. To do so, we investigated their pharmacological characteristics, using in silico tests that indicate likelihood of activity or inactivity, with the PASS online software, and the antimicrobial potential against Gram positive and Gram negative bacteria was also analyzed, including bacteria of clinical importance...
May 24, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28535049/unusual-undergraduate-training-in-medicinal-chemistry-in-collaboration-between-academia-and-industry
#3
Thomas McInally, Simon J F Macdonald
Globalization has driven new paradigms for drug discovery and development. Activities previously carried out predominantly in the United States, Europe, and Japan are now carried out globally. This has caused considerable change in large pharma including how medicinal chemists are trained. Described here is the training of chemistry undergraduates in medicinal chemistry (as practiced in industry) in two modules developed in collaboration between the University of Nottingham (UoN) and GlaxoSmithKline (GSK). The students complete several design-synthesize-test iterations on medicinal chemistry projects where they carry out the design and synthesis, and GSK tests the compounds...
May 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28534261/the-role-of-drug-metabolites-in-the-inhibition-of-cytochrome-p450-enzymes
#4
Momir Mikov, Maja Đanić, Nebojša Pavlović, Bojan Stanimirov, Svetlana Goločorbin-Kon, Karmen Stankov, Hani Al-Salami
Following the drug administration, patients are exposed not only to the parent drug itself, but also to the metabolites generated by drug-metabolizing enzymes. The role of drug metabolites in cytochrome P450 (CYP) inhibition and subsequent drug-drug interactions (DDIs) have recently become a topic of considerable interest and scientific debate. The list of metabolites that were found to significantly contribute to clinically relevant DDIs is constantly being expanded and reported in the literature. New strategies have been developed for better understanding how different metabolites of a drug candidate contribute to its pharmacokinetic properties and pharmacological as well as its toxicological effects...
May 22, 2017: European Journal of Drug Metabolism and Pharmacokinetics
https://www.readbyqxmd.com/read/28533120/evaluation-of-new-chemical-entities-as-substrates-of-liver-transporters-in-the-pharmaceutical-industry-response-to-regulatory-requirements-and-future-steps
#5
Noriko Okudaira
This article discusses the evaluation of drug candidates as hepatic transporter substrates. Recently, research on the applications of hepatic transporters in the pharmaceutical industry has improved to meet the requirements of the regulatory guidelines for the evaluation of drug interactions. To identify the risk of transporter-mediated drug-drug interactions (DDIs) at an early stage of drug development, we employed a strategy of reviewing the in vivo animal pharmacokinetics and tissue distribution data obtained in the discovery stage together with the in vitro data obtained for regulatory submission...
May 19, 2017: Journal of Pharmaceutical Sciences
https://www.readbyqxmd.com/read/28532213/what-do-structures-tell-us-about-chemokine-receptor-function-and-antagonism
#6
Irina Kufareva, Martin Gustavsson, Yi Zheng, Bryan S Stephens, Tracy M Handel
Chemokines and their cell surface G protein-coupled receptors are critical for cell migration, not only in many fundamental biological processes but also in inflammatory diseases and cancer. Recent X-ray structures of two chemokines complexed with full-length receptors provided unprecedented insight into the atomic details of chemokine recognition and receptor activation, and computational modeling informed by new experiments leverages these insights to gain understanding of many more receptor:chemokine pairs...
May 22, 2017: Annual Review of Biophysics
https://www.readbyqxmd.com/read/28531912/from-bench-to-market-preparing-human-pluripotent-stem-cells-derived-cardiomyocytes-for-various-applications
#7
REVIEW
Sung-Hwan Moon, Daekyeong Bae, Taek-Hee Jung, Eun-Bin Chung, Young-Hoon Jeong, Soon-Jung Park, Hyung-Min Chung
Human cardiomyocytes (CMs) cease to proliferate and remain terminally differentiated thereafter, when humans reach the mid-20s. Thus, any damages sustained by myocardium tissue are irreversible, and they require medical interventions to regain functionality. To date, new surgical procedures and drugs have been developed, albeit with limited success, to treat various heart diseases including myocardial infarction. Hence, there is a pressing need to develop more effective treatment methods to address the increasing mortality rate of the heart diseases...
May 30, 2017: International Journal of Stem Cells
https://www.readbyqxmd.com/read/28530853/designing-clinical-trials-that-accept-new-arms-an-example-in-metastatic-breast-cancer
#8
Steffen Ventz, Brian M Alexander, Giovanni Parmigiani, Richard D Gelber, Lorenzo Trippa
Purpose The majority of randomized oncology trials are two-arm studies that test the efficacy of new therapies against a standard of care, thereby assigning a large proportion of patients to nonexperimental therapies. In contrast, multiarm studies efficiently share a common control arm while evaluating multiple experimental therapies. A major bottleneck for traditional multiarm trials is the requirement that all therapies-often drugs from different companies-have to be available at the same time when the trial starts...
May 22, 2017: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/28530546/the-role-of-qsar-and-virtual-screening-studies-in-type-2-diabetes-drug-discovery
#9
Simone Q Pantaleão, Drielli G V Fujji, Vinícius G Maltarollo, Danielle da C Silva, Gustavo H G Trossini, Karen C Weber, Luis P B Scott, Kathia M Honorio
BACKGROUND: Due to the increasing number of diabetes cases worldwide, there is an international concern to provide even more effective treatments to control this condition. METHODS: This review brings together a selection of studies that helped to broaden the comprehension of various biological targets and associated mechanisms involved in type 2 diabetes mellitus. RESULTS: Such studies demonstrated that QSAR techniques and virtual screenings have been successfully employed in drug design projects...
May 22, 2017: Medicinal Chemistry
https://www.readbyqxmd.com/read/28529069/cholinergic-modulation-of-the-immune-system-presents-new-approaches-for-treating-inflammation
#10
REVIEW
Donald B Hoover
The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals...
May 18, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28528876/modeling-covalent-modifier-drugs
#11
REVIEW
Ernest Awoonor-Williams, Andrew G Walsh, Christopher N Rowley
In this review, we present a summary of how computer modeling has been used in the development of covalent modifier drugs. Covalent modifier drugs bind by forming a chemical bond with their target. This covalent binding can improve the selectivity of the drug for a target with complementary reactivity and result in increased binding affinities due to the strength of the covalent bond formed. In some cases, this results in irreversible inhibition of the target, but some targeted covalent inhibitor (TCI) drugs bind covalently but reversibly...
May 18, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28528670/glycine-receptor-drug-discovery
#12
Joseph W Lynch, Yan Zhang, Sahil Talwar, Argel Estrada-Mondragon
Postsynaptic glycine receptor (GlyR) chloride channels mediate inhibitory neurotransmission in the spinal cord and brain stem, although presynaptic and extrasynaptic GlyRs are expressed more widely throughout the brain. In humans, GlyRs are assembled as homo- or heteromeric pentamers of α1-3 and β subunits. GlyR malfunctions have been linked to a range of neurological disorders including hyperekplexia, temporal lobe epilepsy, autism, breathing disorders, and chronic inflammatory pain. Although it is possible that GlyRs may eventually be clinically targeted for a variety of neurological disorders, most research to date has focused on developing GlyR-targeted treatments for chronic pain...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28528667/genetically-encoded-calcium-indicators-as-probes-to-assess-the-role-of-calcium-channels-in-disease-and-for-high-throughput-drug-discovery
#13
John J Bassett, Gregory R Monteith
The calcium ion (Ca(2+)) is an important signaling molecule implicated in many cellular processes, and the remodeling of Ca(2+) homeostasis is a feature of a variety of pathologies. Typical methods to assess Ca(2+) signaling in cells often employ small molecule fluorescent dyes, which are sometimes poorly suited to certain applications such as assessment of cellular processes, which occur over long periods (hours or days) or in vivo experiments. Genetically encoded calcium indicators are a set of tools available for the measurement of Ca(2+) changes in the cytosol and subcellular compartments, which circumvent some of the inherent limitations of small molecule Ca(2+) probes...
2017: Advances in Pharmacology
https://www.readbyqxmd.com/read/28528648/copper-and-antibiotics-discovery-modes-of-action-and-opportunities-for-medicinal-applications
#14
Alex G Dalecki, Cameron L Crawford, Frank Wolschendorf
Copper is a ubiquitous element in the environment as well as living organisms, with its redox capabilities and complexation potential making it indispensable for many cellular functions. However, these same properties can be highly detrimental to prokaryotes and eukaryotes when not properly controlled, damaging many biomolecules including DNA, lipids, and proteins. To restrict free copper concentrations, all bacteria have developed mechanisms of resistance, sequestering and effluxing labile copper to minimize its deleterious effects...
2017: Advances in Microbial Physiology
https://www.readbyqxmd.com/read/28528302/nanomolar-anti-sickling-compounds-identified-by-ligand-based-pharmacophore-approach
#15
Odailson Santos Paz, Milena de Jesus Pinheiro, Renan Fernandes do Espirito Santo, Cristiane Flora Villarreal, Marcelo Santos Castilho
Adenosine receptors are considered as potential targets for drug development against several diseases. The discovery of subtype 2B adenosine receptors role in erythrocyte sickling process proved its importance to neglected diseases such as sickle cell anemia, which affects approximately 29.000 people around the world, but whose treatment is restricted to just one FDA approved drug (hydroxyurea). In order to widen the therapeutic arsenal available to treat sickle cell anemia patients, it is imperative to identify new lead compounds that modify the sickling course and not just its symptoms...
May 12, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28527344/harnessing-plant-metabolic-diversity
#16
REVIEW
Charlie Owen, Nicola J Patron, Ancheng Huang, Anne Osbourn
Advances in DNA sequencing and synthesis technologies in the twenty-first century are now making it possible to build large-scale pipelines for engineering plant natural product pathways into heterologous production species using synthetic biology approaches. The ability to decode the chemical potential of plants by sequencing their transcriptomes and/or genomes and to then use this information as an instruction manual to make drugs and other high-value chemicals is opening up new routes to harness the vast chemical diversity of the Plant Kingdom...
May 17, 2017: Current Opinion in Chemical Biology
https://www.readbyqxmd.com/read/28526744/combining-properties-of-different-classes-of-pi3k%C3%AE-inhibitors-to-understand-molecular-features-that-confer-selectivity
#17
Grace Q Gong, Jackie D Kendall, James Mj Dickson, Gordon W Rewcastle, Christina M Buchanan, William A Denny, Peter R Shepherd, Jack U Flanagan
Phosphoinositide 3-kinases (PI3K) are major regulators of many cellular functions, and hyperactivation of PI3K cell signalling pathways is a major target for anticancer drug discovery. PI3Kα is the isoform most implicated in cancer, and our aim is to selectively inhibit this isoform, which may be more beneficial than concurrent inhibition of all Class I PI3Ks. We have used structure-guided design to merge high selectivity and high affinity characteristics found in existing compounds. Molecular docking including the prediction of water-mediated interactions, was used to model interactions between the ligands and the PI3Kα affinity pocket...
May 19, 2017: Biochemical Journal
https://www.readbyqxmd.com/read/28526617/cyclin-dependent-kinase-5-a-novel-avenue-for-alzheimer-s-disease
#18
REVIEW
Anisha S Bhounsule, Lokesh Kumar Bhatt, Kedar S Prabhavalkar, Manisha Oza
Alzheimer's disease (AD) is one of the most frequently encountered diseases in adults with progressive loss of memory and behavioral changes. Inspite of there being an intense research in the field of AD, only a few chemical entities exhibiting anti-AD activity make it through the clinical trials and it is thus need of an hour to develop new drugs or repurpose the existing ones for better management of Alzheimer's disease. Novel therapeutic targets can influence drug discovery in the field of AD. Cyclin Dependent Kinase 5 (Cdk5) which is a serine/threonine kinase can prove to be an upcoming beneficial target to be studied for treating AD...
May 17, 2017: Brain Research Bulletin
https://www.readbyqxmd.com/read/28525953/human-yeast-hybrids-new-visions-to-genetic-disorders-and-drug-discovery
#19
Najmeh Zarei, Vahid Khalaj
Yeast has been a very helpful organism for centuries, especially with respect to fermentation of sugars and production of bread. However, for an even longer time, yeast has been a distant relative of humans having diverged from a common ancestor, about one billion years ago. More than one third of the yeast genes have human counterparts, despite this evolutionary distance. Yeast and human orthologs perform the same or similar functions. Investigations have demonstrated that 9-92% of the amino acid sequences in similar human and yeast proteins overlap...
July 2017: Iranian Biomedical Journal
https://www.readbyqxmd.com/read/28525765/covalent-probe-finds-carboxylic-acid
#20
Alexander Jones, Xiaoyun Zhang, Xiaoguang Lei
In this issue of Cell Chemical Biology, Martín-Gago et al. (2017a) disclose a new strategy for the selective covalent targeting of binding site carboxylic acids within the proteome using the isoxazolium salt as a warhead. This discovery paves the way for developing new protein ligation methods as well as covalent drug candidates.
May 18, 2017: Cell Chemical Biology
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