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https://www.readbyqxmd.com/read/28437733/the-establishment-of-in%C3%A2-vitro-culture-and-drug-screening-systems-for-a-newly-isolated-strain-of-trypanosoma-equiperdum
#1
Keisuke Suganuma, Shino Yamasaki, Nthatisi Innocentia Molefe, Peter Simon Musinguzi, Batdorj Davaasuren, Ehab Mossaad, Sandagdorj Narantsatsral, Banzragch Battur, Badgar Battsetseg, Noboru Inoue
Dourine is caused by Trypanosoma equiperdum via coitus with an infected horse. Although dourine is distributed in Equidae worldwide and is listed as an internationally important animal disease by the World Organization for Animal Health (OIE), no effective treatment strategies have been established. In addition, there are no reports on drug discovery, because no drug screening system exists for this parasite. A new T. equiperdum strain was recently isolated from the genital organ of a stallion that showed typical symptoms of dourine...
April 13, 2017: International Journal for Parasitology, Drugs and Drug Resistance
https://www.readbyqxmd.com/read/28437091/speeding-up-early-drug-discovery-in-antiviral-research-a-fragment-based-in-silico-approach-for-the-design-of-virtual-anti-hepatitis-c-leads
#2
Alejandro Speck-Planche, M Natalia Dias Soeiro Cordeiro
Hepatitis C constitutes an unresolved global health problem. This infectious disease is caused by the hepatotropic hepatitis C virus (HCV), and it can lead to the occurrence of life-threatening medical conditions such as cirrhosis and liver cancer. Nowadays, major clinical concerns have arisen due to the appearance of multidrug resistance (MDR), and the side effects especially associated with long-term treatments. In this work, we report the first multitasking model for quantitative structure-biological effect relationships (mtk-QSBER), focused on the simultaneous exploration of anti-HCV activity and in vitro safety profiles related to the absorption, distribution, metabolism, elimination, and toxicity (ADMET)...
April 24, 2017: ACS Combinatorial Science
https://www.readbyqxmd.com/read/28436443/curcumol-allosterically-modulates-gaba-a-receptors-in-a-manner-distinct-from-benzodiazepines
#3
Yan-Mei Liu, Hui-Ran Fan, Jing Ding, Chen Huang, Shining Deng, Tailin Zhu, Tian-Le Xu, Wei-Hong Ge, Wei-Guang Li, Fei Li
Inhibitory A type γ-aminobutyric acid receptors (GABAARs) play a pivotal role in orchestrating various brain functions and represent an important molecular target in neurological and psychiatric diseases, necessitating the need for the discovery and development of novel modulators. Here, we show that a natural compound curcumol, acts as an allosteric enhancer of GABAARs in a manner distinct from benzodiazepines. Curcumol markedly facilitated GABA-activated currents and shifted the GABA concentration-response curve to the left in cultured hippocampal neurons...
April 24, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28436314/metabolomic-approaches-in-the-discovery-of-potential-urinary-biomarkers-of-drug-induced-liver-injury-dili
#4
Ana Margarida Araújo, Márcia Carvalho, Félix Carvalho, Maria de Lourdes Bastos, Paula Guedes de Pinho
Drug-induced liver injury (DILI) is a major safety issue during drug development, as well as the most common cause for the withdrawal of drugs from the pharmaceutical market. The identification of DILI biomarkers is a labor-intensive area. Conventional biomarkers are not specific and often only appear at significant levels when liver damage is substantial. Therefore, new biomarkers for early identification of hepatotoxicity during the drug discovery process are needed, thus resulting in lower development costs and safer drugs...
April 24, 2017: Critical Reviews in Toxicology
https://www.readbyqxmd.com/read/28435533/discovery-of-antimalarial-azetidine-2-carbonitriles-that-inhibit-p-falciparum-dihydroorotate-dehydrogenase
#5
Micah Maetani, Nobutaka Kato, Valquiria A P Jabor, Felipe A Calil, Maria Cristina Nonato, Christina A Scherer, Stuart L Schreiber
Dihydroorotate dehydrogenase (DHODH) is an enzyme necessary for pyrimidine biosynthesis in protozoan parasites of the genus Plasmodium, the causative agents of malaria. We recently reported the identification of novel compounds derived from diversity-oriented synthesis with activity in multiple stages of the malaria parasite life cycle. Here, we report the optimization of a potent series of antimalarial inhibitors consisting of azetidine-2-carbonitriles, which we had previously shown to target P. falciparum DHODH in a biochemical assay...
April 13, 2017: ACS Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28434763/computer-aided-discovery-of-two-novel-chalcone-like-compounds-active-and-selective-against-leishmania-infantum
#6
Marcelo N Gomes, Laura M Alcântara, Bruno J Neves, Cleber C Melo-Filho, Lucio H Freitas-Junior, Carolina B Moraes, Rui Ma, Scott G Franzblau, Eugene Muratov, Carolina Horta Andrade
Leishmaniasis are infectious diseases caused by parasites of genus Leishmania that affect affects 12 million people in 98 countries mainly in Africa, Asia, and Latin America. Effective treatments for this disease are urgently needed. In this study, we present a computer-aided approach to investigate a set of 32 recently synthesized chalcone and chalcone-like compounds to act as antileishmanial agents. As a result, nine most promising compounds and three potentially inactive compounds were experimentally evaluated against Leishmania infantum amastigotes and mammalian cells...
April 4, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28434587/aligning-physiology-with-psychology-translational-neuroscience-in-neuropsychiatric-drug-discovery
#7
REVIEW
Robert A McArthur
This review presents an overview of some of the pre-clinical and clinical issues that have contributed to the failures of potential novel neuropsychiatric drugs, which have prompted a re-examination of the role of animal models of neuropsychiatric disorders. Advances both in basic neuroscience and technology have driven the development of animal models of aspects of neuropsychiatric disorders. Genetics and environmental factors have been the primary contributors to the development of new animal models. Neuroimaging has contributed to the search for biomarkers by which neuropsychiatric disorders may be identified and differentiated, its progression monitored and that the effects of therapy assessed...
May 2017: Neuroscience and Biobehavioral Reviews
https://www.readbyqxmd.com/read/28433481/genetics-of-common-complex-diseases-a-view-from-iceland
#8
REVIEW
David O Arnar, Runolfur Palsson
In the past decade, large scale genotyping has led to discoveries of numerous sequence variants that confer increased risk of many common complex diseases. Interestingly, a substantial proportion of pioneering genetic work has originated from the small nation of Iceland and has been facilitated by an extensive genealogy database. We provide examples of relevant observations made so far in several major disease categories central to internal medicine practice. Some of these findings offer new mechanistic clues into the pathophysiology of common disorders and may suggest novel approaches in diagnosis and drug therapy...
April 19, 2017: European Journal of Internal Medicine
https://www.readbyqxmd.com/read/28432980/discovery-of-potential-inhibitor-against-human-acetylcholinesterase-a-molecular-docking-and-molecular-dynamics-investigation
#9
Surya Pratap Singh, Dwijendra Gupta
Alzheimer's disease (AD) is a progressive neurodegenerative disease of central nervous system among elderly people. Human acetylcholinesterase (hAChE), an important enzyme in neuronal signaling, is responsible for the degradation of acetylcholine which in turn prevents the post synaptic signal transmissions. hAChE has been an attractive target of drug discovery for the search of therapeutics against AD. In the recent past hAChE has become hot target for the investigation of new potential therapeutics. We performed virtual screening of entire database against hAChE...
April 12, 2017: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/28431353/discovery-of-potential-anticancer-multi-targeted-ligustrazine-based-cyclohexanone-and-oxime-analogs-overcoming-the-cancer-multidrug-resistance
#10
Gao-Feng Zha, Hua-Li Qin, Bahaa G M Youssif, Muhammad Wahab Amjad, Maria Abdul Ghafoor Raja, Ahmed H Abdelazeem, Syed Nasir Abbas Bukhari
The drug research and development nowadays is focusing on multi-target drugs. In the treatment of cancer, therapies using drugs inhibiting one numerous targets signify a novel viewpoint. In comparison with traditional therapy, multi-targeted drugs directly aim cell subpopulations which are involved in progression of tumor. The current study comprises the synthesis of 34 novel ligustrazine-containing α, β-unsaturated carbonyl-based compounds and oximes. The growth of 5 various cancer cell types was strongly inhibited by ligustrazine-containing oximes as revealed by biological evaluation...
April 14, 2017: European Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28427795/reappraisal-to-the-study-of-4e-bp1-as-an-mtor-substrate-a-normative-critique
#11
REVIEW
Asiya Batool, Sabreena Aashaq, Khurshid Iqbal Andrabi
mTOR-4E-BP1 axis is regarded as the best oncogenic circuitry impinging on translational control whereby mTORC1 dictates post-translational regulation of 4E-BP1. This review provides new insights into the molecular network of signalling pathways highlighting the recent explosion of studies in respect to the deviant behaviour of 4E-BP1 towards mTORC1. Despite the striking conservation of mTOR nexus, the eccentric phosphorylation dynamics of 4E-BP1 negate the apparent linear architecture of mTORC1 attesting the importance of other kinases that may evoke cross-talks with the conventional frame, most of which are enlisted in the manuscript...
April 8, 2017: European Journal of Cell Biology
https://www.readbyqxmd.com/read/28427436/a-3d-in-vitro-model-of-the-human-breast-duct-a-method-to-unravel-myoepithelial-luminal-interactions-in-the-progression-of-breast-cancer
#12
Edward P Carter, James A Gopsill, Jennifer J Gomm, J Louise Jones, Richard P Grose
BACKGROUND: 3D modelling fulfils a critical role in research, allowing for complex cell behaviour and interactions to be studied in physiomimetic conditions. With tissue banks becoming established for a number of cancers, researchers now have access to primary patient cells, providing the perfect building blocks to recreate and interrogate intricate cellular systems in the laboratory. The ducts of the human breast are composed of an inner layer of luminal cells supported by an outer layer of myoepithelial cells...
April 21, 2017: Breast Cancer Research: BCR
https://www.readbyqxmd.com/read/28426203/tyrosine-kinase-activation-and-conformational-flexibility-lessons-from-src-family-tyrosine-kinases
#13
Yilin Meng, Matthew P Pond, Benoît Roux
Protein kinases are enzymes that catalyze the covalent transfer of the γ-phosphate of an adenosine triphosphate (ATP) molecule onto a tyrosine, serine, threonine, or histidine residue in the substrate and thus send a chemical signal to networks of downstream proteins. They are important cellular signaling enzymes that regulate cell growth, proliferation, metabolism, differentiation, and migration. Unregulated protein kinase activity is often associated with a wide range of diseases, therefore making protein kinases major therapeutic targets...
April 20, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28425720/a-cereblon-modulator-cc-220-with-improved-degradation-of-ikaros-and-aiolos
#14
Mary E Matyskiela, Weihong Zhang, Hon-Wah Man, George Muller, Godrej Khambatta, Frans Baculi, Matthew Hickman, Laurie LeBrun, Barbra Pagarigan, Gilles Carmel, Chin-Chun Lu, Gang Lu, Mariko Riley, Yoshitaka Satoh, Peter Schafer, Thomas O Daniel, James Carmichael, Brian E Cathers, Philip P Chamberlain
The drugs lenalidomide and pomalidomide bind to the protein cereblon, directing the CRL4-CRBN E3 ligase toward the transcription factors Ikaros and Aiolos to cause their ubiquitination and degradation. Here we describe CC-220 (compound 6), a cereblon modulator in clinical development for systemic lupus erythematosis and relapsed/refractory multiple myeloma. Compound 6 binds cereblon with a higher affinity than lenalidomide or pomalidomide. Consistent with this, the cellular degradation of Ikaros and Aiolos is more potent and the extent of substrate depletion is greater...
April 20, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28425478/data-intensive-genome-level-analysis-for-identifying-novel-non-toxic-drug-targets-for-multi-drug-resistant-mycobacterium-tuberculosis
#15
Divneet Kaur, Rintu Kutum, Debasis Dash, Samir K Brahmachari
We report the construction of a novel Systems Biology based virtual drug discovery model for the prediction of non-toxic metabolic targets in Mycobacterium tuberculosis (Mtb). This is based on a data-intensive genome level analysis and the principle of conservation of the evolutionarily important genes. In the 1623 sequenced Mtb strains, 890 metabolic genes identified through a systems approach in Mtb were evaluated for non-synonymous mutations. The 33 genes showed none or one variation in the entire 1623 strains, including 1084 Russian MDR strains...
April 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28424617/targeting-bile-acid-receptors-discovery-of-a-potent-and-selective-farnesoid-x-receptor-agonist-as-a-new-lead-in-the-pharmacological-approach-to-liver-diseases
#16
Carmen Festa, Simona De Marino, Adriana Carino, Valentina Sepe, Silvia Marchianò, Sabrina Cipriani, Francesco S Di Leva, Vittorio Limongelli, Maria C Monti, Angela Capolupo, Eleonora Distrutti, Stefano Fiorucci, Angela Zampella
Bile acid (BA) receptors represent well-defined targets for the development of novel therapeutic approaches to metabolic and inflammatory diseases. In the present study, we report the generation of novel C-3 modified 6-ethylcholane derivatives. The pharmacological characterization and molecular docking studies for the structure-activity rationalization, allowed the identification of 3β-azido-6α-ethyl-7α-hydroxy-5β-cholan-24-oic acid (compound 2), a potent and selective FXR agonist with a nanomolar potency in transactivation assay and high efficacy in the recruitment of SRC-1 co-activator peptide in Alfa Screen assay...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28424538/metal-complexes-in-cancer-therapy-an-update-from-drug-design-perspective
#17
REVIEW
Umar Ndagi, Ndumiso Mhlongo, Mahmoud E Soliman
In the past, metal-based compounds were widely used in the treatment of disease conditions, but the lack of clear distinction between the therapeutic and toxic doses was a major challenge. With the discovery of cisplatin by Barnett Rosenberg in 1960, a milestone in the history of metal-based compounds used in the treatment of cancers was witnessed. This forms the foundation for the modern era of the metal-based anticancer drugs. Platinum drugs, such as cisplatin, carboplatin and oxaliplatin, are the mainstay of the metal-based compounds in the treatment of cancer, but the delay in the therapeutic accomplishment of other metal-based compounds hampered the progress of research in this field...
2017: Drug Design, Development and Therapy
https://www.readbyqxmd.com/read/28423600/systematic-screening-of-isogenic-cancer-cells-identifies-dusp6-as-context-specific-synthetic-lethal-target-in-melanoma
#18
Stephanie Wittig-Blaich, Rainer Wittig, Steffen Schmidt, Stefan Lyer, Melanie Bewerunge-Hudler, Sabine Gronert-Sum, Olga Strobel-Freidekind, Carolin Müller, Markus List, Aleksandra Jaskot, Helle Christiansen, Mathias Hafner, Dirk Schadendorf, Ines Block, Jan Mollenhauer
Next-generation sequencing has dramatically increased genome-wide profiling options and conceptually initiates the possibility for personalized cancer therapy. State-of-the-art sequencing studies yield large candidate gene sets comprising dozens or hundreds of mutated genes. However, few technologies are available for the systematic downstream evaluation of these results to identify novel starting points of future cancer therapies.We improved and extended a site-specific recombination-based system for systematic analysis of the individual functions of a large number of candidate genes...
April 4, 2017: Oncotarget
https://www.readbyqxmd.com/read/28422298/bridging-type-2-diabetes-and-alzheimer-s-disease-assembling-the-puzzle-pieces-in-the-quest-for-the-molecules-with-therapeutic-and-preventive-potential
#19
REVIEW
Ana Marta de Matos, Maria Paula de Macedo, Amélia Pilar Rauter
Type 2 diabetes (T2D) and Alzheimer's disease (AD) are two age-related amyloid diseases that affect millions of people worldwide. Broadly supported by epidemiological data, the higher incidence of AD among type 2 diabetic patients led to the recognition of T2D as a tangible risk factor for the development of AD. Indeed, there is now growing evidence on brain structural and functional abnormalities arising from brain insulin resistance and deficiency, ultimately highlighting the need for new approaches capable of preventing the development of AD in type 2 diabetic patients...
April 19, 2017: Medicinal Research Reviews
https://www.readbyqxmd.com/read/28421296/metabolite-signatures-of-doxorubicin-induced-toxicity-in-human-induced-pluripotent-stem-cell-derived-cardiomyocytes
#20
Umesh Chaudhari, James K Ellis, Vilas Wagh, Harshal Nemade, Jürgen Hescheler, Hector C Keun, Agapios Sachinidis
Drug-induced off-target cardiotoxicity, particularly following anti-cancer therapy, is a major concern in new drug discovery and development. To ensure patient safety and efficient pharmaceutical drug development, there is an urgent need to develop more predictive cell model systems and distinct toxicity signatures. In this study, we applied our previously proposed repeated exposure toxicity methodology and performed (1)H NMR spectroscopy-based extracellular metabolic profiling in culture medium of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) exposed to doxorubicin (DOX), an anti-cancer agent...
April 18, 2017: Amino Acids
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