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Target tractability

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https://www.readbyqxmd.com/read/28714473/prioritizing-multiple-therapeutic-targets-in-parallel-using-automated-dna-encoded-library-screening
#1
Carl A Machutta, Christopher S Kollmann, Kenneth E Lind, Xiaopeng Bai, Pan F Chan, Jianzhong Huang, Lluis Ballell, Svetlana Belyanskaya, Gurdyal S Besra, David Barros-Aguirre, Robert H Bates, Paolo A Centrella, Sandy S Chang, Jing Chai, Anthony E Choudhry, Aaron Coffin, Christopher P Davie, Hongfeng Deng, Jianghe Deng, Yun Ding, Jason W Dodson, David T Fosbenner, Enoch N Gao, Taylor L Graham, Todd L Graybill, Karen Ingraham, Walter P Johnson, Bryan W King, Christopher R Kwiatkowski, Joël Lelièvre, Yue Li, Xiaorong Liu, Quinn Lu, Ruth Lehr, Alfonso Mendoza-Losana, John Martin, Lynn McCloskey, Patti McCormick, Heather P O'Keefe, Thomas O'Keeffe, Christina Pao, Christopher B Phelps, Hongwei Qi, Keith Rafferty, Genaro S Scavello, Matt S Steiginga, Flora S Sundersingh, Sharon M Sweitzer, Lawrence M Szewczuk, Amy Taylor, May Fern Toh, Juan Wang, Minghui Wang, Devan J Wilkins, Bing Xia, Gang Yao, Jean Zhang, Jingye Zhou, Christine P Donahue, Jeffrey A Messer, David Holmes, Christopher C Arico-Muendel, Andrew J Pope, Jeffrey W Gross, Ghotas Evindar
The identification and prioritization of chemically tractable therapeutic targets is a significant challenge in the discovery of new medicines. We have developed a novel method that rapidly screens multiple proteins in parallel using DNA-encoded library technology (ELT). Initial efforts were focused on the efficient discovery of antibacterial leads against 119 targets from Acinetobacter baumannii and Staphylococcus aureus. The success of this effort led to the hypothesis that the relative number of ELT binders alone could be used to assess the ligandability of large sets of proteins...
July 17, 2017: Nature Communications
https://www.readbyqxmd.com/read/28705643/gpcrs-and-egfr-cross-talk-of-membrane-receptors-in-cancer
#2
REVIEW
Meryem Köse
G protein-coupled receptors (GPCRs) and receptor-tyrosine kinases (RTKs) are two important classes of cell surface receptors proven to be highly tractable as drug targets. Both receptor classes are involved in various complex (patho-) physiological processes in the human body including cellular growth and differentiation. More recently, accumulating data suggest that GPCR-induced activation of EGFR, the prototyp of RTKs represents a major mechanism in various cancers. The present review will focus on this cross-talk with particular emphasis on intracellular scaffold proteins regulating EGFR transactivation...
July 3, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28696692/evaluating-force-field-performance-in-thermodynamic-calculations-of-cyclodextrin-host-guest-binding-water-models-partial-charges-and-host-force-field-parameters
#3
Niel M Henriksen, Michael K Gilson
Computational prediction of noncovalent binding free energies with methods based on molecular mechanical force fields has become increasingly routine in drug discovery projects, where they promise to speed the discovery of small molecule ligands to bind targeted proteins with high affinity. Because the reliability of free energy methods still has significant room for improvement, new force fields, or modifications of existing ones, are regularly introduced with the aim of improving the accuracy of molecular simulations...
July 11, 2017: Journal of Chemical Theory and Computation
https://www.readbyqxmd.com/read/28681041/next-generation-sequencing-reveals-potentially-actionable-alterations-in-the-majority-of-patients-with-lymphoid-malignancies
#4
Aaron M Goodman, Michael Choi, Matthew Wieduwilt, Carolyn Mulroney, Caitlin Costello, Garrett Frampton, Vincent Miller, Razelle Kurzrock
Next generation sequencing (NGS) identifies alterations that may be potentially targetable by Food and Drug Administration (FDA) approved drugs and/or by available experimental agents that may not have otherwise been contemplated. Many targeted drugs have been developed for diverse solid cancers; a smaller number of genomically targeted drugs have been approved for lymphoid malignancies. We analyzed NGS results from 60 patients with various lymphoid malignancies and found a total of 224 alterations (median per patient = 3)...
June 2017: JCO Precis Oncol
https://www.readbyqxmd.com/read/28679595/poor-sleep-is-associated-with-csf-biomarkers-of-amyloid-pathology-in-cognitively-normal-adults
#5
Kate E Sprecher, Rebecca L Koscik, Cynthia M Carlsson, Henrik Zetterberg, Kaj Blennow, Ozioma C Okonkwo, Mark A Sager, Sanjay Asthana, Sterling C Johnson, Ruth M Benca, Barbara B Bendlin
OBJECTIVE: To determine the relationship between sleep quality and CSF markers of Alzheimer disease (AD) pathology in late midlife. METHODS: We investigated the relationship between sleep quality and CSF AD biomarkers in a cohort enriched for parental history of sporadic AD, the Wisconsin Registry for Alzheimer's Prevention. A total of 101 participants (mean age 62.9 ± 6.2 years, 65.3% female) completed sleep assessments and CSF collection and were cognitively normal...
July 5, 2017: Neurology
https://www.readbyqxmd.com/read/28644430/the-clinical-landscape-for-sma-in-a-new-therapeutic-era
#6
REVIEW
K Talbot, E F Tizzano
Despite significant advances in basic research, the treatment of degenerative diseases of the nervous system remains one of the greatest challenges for translational medicine. The childhood onset motor neuron disorder spinal muscular atrophy (SMA) has been viewed as one of the more tractable targets for molecular therapy, due to a detailed understanding of the molecular genetic basis of the disease. In SMA, inactivating mutations in the SMN1 gene can be partially compensated for by limited expression of SMN protein from a variable number of copies of the SMN2 gene, which provides both a molecular explanation for phenotypic severity and a target for therapy...
June 23, 2017: Gene Therapy
https://www.readbyqxmd.com/read/28641214/motor-system-dysfunction-in-the-schizophrenia-diathesis-neural-systems-to-neurotransmitters
#7
R Abboud, C Noronha, V A Diwadkar
Motor control is a ubiquitous aspect of human function, and from its earliest origins, abnormal motor control has been proposed as being central to schizophrenia. The neurobiological architecture of the motor system is well understood in primates and involves cortical and sub-cortical components including the primary motor cortex, supplementary motor area, dorsal anterior cingulate cortex, the prefrontal cortex, the basal ganglia, and cerebellum. Notably all of these regions are associated in some manner to the pathophysiology of schizophrenia...
April 25, 2017: European Psychiatry: the Journal of the Association of European Psychiatrists
https://www.readbyqxmd.com/read/28637759/role-of-jnk-pathway-in-varicella-zoster-virus-lytic-infection-and-reactivation
#8
Sravya Kurapati, Tomohiko Sadaoka, Labchan Rajbhandari, Balaji Jagdish, Priya Shukla, Yong Jun Kim, Gabsang Lee, Jeffrey I Cohen, Arun Venkatesan
Mechanisms of neuronal infection by varicella-zoster virus (VZV) have been challenging to study due to the relatively strict human tropism of the virus and the paucity of tractable experimental models. Cellular mitogen activated protein kinases (MAPKs) have been shown to play a role in VZV infection of non-neuronal cells, with distinct consequences on infectivity in differing cell types. Here, we utilize several human neuronal culture systems to investigate the role of one such MAPK, the c-Jun N-terminal kinase (JNK), in VZV lytic infection and reactivation...
June 21, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28633205/advancing-the-science-of-myocardial-recovery-with-mechanical-circulatory-support-a-working-group-of-the-national-heart-lung-and-blood-institute
#9
EDITORIAL
Stavros G Drakos, Francis D Pagani, Martha S Lundberg, Timothy J Baldwin
The medical burden of heart failure (HF) has spurred interest in clinicians and scientists to develop therapies to restore the function of a failing heart. To advance this agenda, the National Heart, Lung, and Blood Institute (NHLBI) convened a Working Group of experts from June 2 to 3, 2016, in Bethesda, Maryland, to develop NHLBI recommendations aimed at advancing the science of cardiac recovery in the setting of mechanical circulatory support (MCS). MCS devices effectively reduce volume and pressure overload that drives the cycle of progressive myocardial dysfunction, thereby triggering structural and functional reverse remodeling...
July 2017: Journal of Thoracic and Cardiovascular Surgery
https://www.readbyqxmd.com/read/28630153/membrane-spanning-%C3%AE-helical-barrels-as-tractable-protein-design-targets
#10
REVIEW
Ai Niitsu, Jack W Heal, Kerstin Fauland, Andrew R Thomson, Derek N Woolfson
The rational (de novo) design of membrane-spanning proteins lags behind that for water-soluble globular proteins. This is due to gaps in our knowledge of membrane-protein structure, and experimental difficulties in studying such proteins compared to water-soluble counterparts. One limiting factor is the small number of experimentally determined three-dimensional structures for transmembrane proteins. By contrast, many tens of thousands of globular protein structures provide a rich source of 'scaffolds' for protein design, and the means to garner sequence-to-structure relationships to guide the design process...
August 5, 2017: Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences
https://www.readbyqxmd.com/read/28624514/bromodomain-containing-proteins-in-prostate-cancer
#11
REVIEW
Alfonso Urbanucci, Ian G Mills
Several oncogenic factors have been involved in prostate cancer progression. However, therapeutic approaches still focus on suppression of androgen receptor (AR) signaling. In fact, whereas the full-length AR incorporates a ligand-binding domain, which has become a drug target for competitive inhibitors, other transcription factors often do not have tractable binding pockets that aid drug development. Consequently drug development efforts have turned to transcription co-regulators, often chromatin-modifying enzymes or factors that bind to epigenetic modifications to chromatin...
June 14, 2017: Molecular and Cellular Endocrinology
https://www.readbyqxmd.com/read/28619757/cdk4-6-inhibitors-sensitize-rb-positive-sarcoma-cells-to-wee1-kinase-inhibition-through-reversible-cell-cycle-arrest
#12
Ashleigh M Francis, Angela Alexander, Yanna Liu, Smruthi Vijayaraghavan, Kwang Hui Low, Dong Yang, Tuyen Bui, Neeta Somaiah, Vinod Ravi, Khandan Keyomarsi, Kelly K Hunt
Research into the biology of soft tissue sarcomas has uncovered very few effective treatment strategies that improve upon the current standard of care which usually involves surgery, radiation, and chemotherapy. Many patients with large (>5cm), high-grade sarcomas develop recurrence, and at that point have limited treatment options available. One challenge is the heterogeneity of genetic drivers of sarcomas, and many of these are not validated targets. Even when such genes are tractable targets, the rarity of each subtype of sarcoma makes advances in research slow...
June 15, 2017: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/28574981/a-motor-unit-based-model-of-muscle-fatigue
#13
Jim R Potvin, Andrew J Fuglevand
Muscle fatigue is a temporary decline in the force and power capacity of skeletal muscle resulting from muscle activity. Because control of muscle is realized at the level of the motor unit (MU), it seems important to consider the physiological properties of motor units when attempting to understand and predict muscle fatigue. Therefore, we developed a phenomenological model of motor unit fatigue as a tractable means to predict muscle fatigue for a variety of tasks and to illustrate the individual contractile responses of MUs whose collective action determines the trajectory of changes in muscle force capacity during prolonged activity...
June 2017: PLoS Computational Biology
https://www.readbyqxmd.com/read/28560482/integrated-in-silico-fragment-based-drug-design-case-study-with-allosteric-modulators-on-metabotropic-glutamate-receptor-5
#14
Yuemin Bian, Zhiwei Feng, Peng Yang, Xiang-Qun Xie
GPCR allosteric modulators target at the allosteric binding pockets of G protein-coupled receptors (GPCRs) with indirect influence on the effects of an orthosteric ligand. Such modulators exhibit significant advantages compared to the corresponding orthosteric ligands, including better chemical tractability or physicochemical properties, improved selectivity, and reduced risk of oversensitization towards their receptors. Metabotropic glutamate receptor 5 (mGlu5), a member of class C GPCRs, is a promising therapeutic target for treating many central nervous system diseases...
May 30, 2017: AAPS Journal
https://www.readbyqxmd.com/read/28557180/targeting-g-protein-coupled-receptors-by-capture-compound-mass-spectrometry-ccms-a-case-study-with-sertindole
#15
Christian Blex, Simon Michaelis, Anna K Schrey, Jens Furkert, Jenny Eichhorst, Kathrin Bartho, Frederick G Quast, Anett Marais, Matthias Hakelberg, Uschi Gruber, Sylvia Niquet, Oliver Popp, Friedrich Kroll, Michael Sefkow, Ralf Schülein, Dreger Mathias, Hubert Köster
Unbiased chemoproteomic profiling of small molecule interactions with endogenous proteins is important for drug discovery. For meaningful results, all protein classes have to be tractable, including G-protein coupled receptors (GPCRs). These are hardly tractable by affinity pulldown from lysates. We report a Capture Compound (CC)-based strategy to target and identify GPCRs directly from living cells. We synthesized CCs with sertindole attached to the CC scaffold in different orientations to target the dopamine D2 receptor (DRD2) heterologously expressed in HEK293 cells...
May 29, 2017: Chembiochem: a European Journal of Chemical Biology
https://www.readbyqxmd.com/read/28542189/mir-277-4989-regulate-transcriptional-landscape-during-juvenile-to-adult-transition-in-the-parasitic-helminth-schistosoma-mansoni
#16
Anna V Protasio, Stijn van Dongen, Julie Collins, Leonor Quintais, Diogo M Ribeiro, Florian Sessler, Martin Hunt, Gabriel Rinaldi, James J Collins, Anton J Enright, Matthew Berriman
Schistosomes are parasitic helminths that cause schistosomiasis, a disease affecting circa 200 million people, primarily in underprivileged regions of the world. Schistosoma mansoni is the most experimentally tractable schistosome species due to its ease of propagation in the laboratory and the high quality of its genome assembly and annotation. Although there is growing interest in microRNAs (miRNAs) in trematodes, little is known about the role these molecules play in the context of developmental processes...
May 2017: PLoS Neglected Tropical Diseases
https://www.readbyqxmd.com/read/28538159/long-term-stochastic-editing-of-regenerative-anatomy-via-targeting-endogenous-bioelectric-gradients
#17
Fallon Durant, Junji Morokuma, Christopher Fields, Katherine Williams, Dany Spencer Adams, Michael Levin
We show that regenerating planarians' normal anterior-posterior pattern can be permanently rewritten by a brief perturbation of endogenous bioelectrical networks. Temporary modulation of regenerative bioelectric dynamics in amputated trunk fragments of planaria stochastically results in a constant ratio of regenerates with two heads to regenerates with normal morphology. Remarkably, this is shown to be due not to partial penetrance of treatment, but a profound yet hidden alteration to the animals' patterning circuitry...
May 23, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28498102/chimeric-origins-of-ochrophytes-and-haptophytes-revealed-through-an-ancient-plastid-proteome
#18
Richard G Dorrell, Gillian Gile, Giselle McCallum, Raphaël Méheust, Eric P Bapteste, Christen M Klinger, Loraine Brillet-Guéguen, Katalina D Freeman, Daniel J Richter, Chris Bowler
Plastids are supported by a wide range of proteins encoded within the nucleus and imported from the cytoplasm. These plastid-targeted proteins may originate from the endosymbiont, the host, or other sources entirely. Here, we identify and characterise 770 plastid-targeted proteins that are conserved across the ochrophytes, a major group of algae including diatoms, pelagophytes and kelps, that possess plastids derived from red algae. We show that the ancestral ochrophyte plastid proteome was an evolutionary chimera, with 25% of its phylogenetically tractable nucleus-encoded proteins deriving from green algae...
May 12, 2017: ELife
https://www.readbyqxmd.com/read/28489574/targeting-neurokinin-3-receptor-a-novel-anti-angiogenesis-strategy-for-cancer-treatment
#19
Ting Wang, Siwei Chen, Shihui Wang, Liang Shi, Chenggong Wang, Jingxin Zhang, Yanfeng Gao, Guodong Li, Yuanming Qi, Xiuli An, Lixiang Chen
Angiogenesis is essential for tumor growth and metastasis, controlling angiogenesis is a promising strategy in cancer treatment. However, thus farther severe side effects of anti-angiogenic drugs have been rather demonstrated, stimulating interest in seeking novel targets of anti-angiogenesis. Neurokinin receptors, also known as tachykinin receptors, are usually considered as drug targets due to diverse physiological functions and their tractability. Although Neurokinin B, the selective natural agonist of neurokinin-3 receptor, have been shown to exhibit anti-angiogenesis activity, the effect and mechanism of neurokinin-3 receptor-mediated angiogenesis still remains unclear...
June 20, 2017: Oncotarget
https://www.readbyqxmd.com/read/28488276/cntnap2-is-a-direct-foxp2-target-in-vitro-and-in-vivo-in-zebra-finches-complex-regulation-by-age-and-activity
#20
I Adam, E Mendoza, U Kobalz, S Wohlgemuth, C Scharff
Mutations of FOXP2 are associated with altered brain structure, including the striatal part of the basal ganglia, and cause a severe speech and language disorder. Songbirds serve as a tractable neurobiological model for speech and language research. Experimental downregulation of FoxP2 in zebra finch Area X, a nucleus of the striatal song control circuitry, affects synaptic transmission and spine densities. It also renders song learning and production inaccurate and imprecise, similar to the speech impairment of patients carrying FOXP2 mutations...
May 10, 2017: Genes, Brain, and Behavior
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