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https://www.readbyqxmd.com/read/29346437/tissue-specific-transcriptome-analyses-provide-new-insights-into-gpcr-signalling-in-adult-schistosoma-mansoni
#1
REVIEW
Steffen Hahnel, Nic Wheeler, Zhigang Lu, Arporn Wangwiwatsin, Paul McVeigh, Aaron Maule, Matthew Berriman, Timothy Day, Paula Ribeiro, Christoph G Grevelding
Schistosomes are blood-dwelling trematodes with global impact on human and animal health. Because medical treatment is currently based on a single drug, praziquantel, there is urgent need for the development of alternative control strategies. The Schistosoma mansoni genome project provides a platform to study and connect the genetic repertoire of schistosomes to specific biological functions essential for successful parasitism. G protein-coupled receptors (GPCRs) form the largest superfamily of transmembrane receptors throughout the Eumetazoan phyla, including platyhelminths...
January 2018: PLoS Pathogens
https://www.readbyqxmd.com/read/29346071/identification-of-potential-inhibitors-against-nuclear-dam1-complex-subunit-ask1-of-candida-albicans-using-virtual-screening-and-md-simulations
#2
Himanshu Tripathi, Feroz Khan
Identification of hit compounds against specific target form the starting point for a drug discovery program. A consistent decline of new chemical entities (NCEs) in recent years prompted a challenge to explore newer approaches to discover potential hit compounds that in turn can be converted into leads, and ultimately drug with desired therapeutic efficacy. The vast amount of omics and activity data available in public databases offers an opportunity to identify novel targets and their potential inhibitors...
January 1, 2018: Computational Biology and Chemistry
https://www.readbyqxmd.com/read/29345939/discovery-of-alternative-producers-of-the-enediyne-antitumor-antibiotic-c-1027-with-high-titers
#3
Xiaohui Yan, Hindra, Huiming Ge, Dong Yang, Tingting Huang, Ivana Crnovcic, Chin-Yuan Chang, Shi-Ming Fang, Thibault Annaval, Xiangcheng Zhu, Yong Huang, Li-Xing Zhao, Yi Jiang, Yanwen Duan, Ben Shen
The potent cytotoxicity and unique mode of action make the enediyne antitumor antibiotic C-1027 an exquisite drug candidate for anticancer chemotherapy. However, clinical development of C-1027 has been hampered by its low titer from the original producer Streptomyces globisporus C-1027. Here we report three new C-1027 alternative producers, Streptomyces sp. CB00657, CB02329, and CB03608, from The Scripps Research Institute actinomycetes strain collection. Together with the previously disclosed Streptomyces sp...
January 18, 2018: Journal of Natural Products
https://www.readbyqxmd.com/read/29345897/design-synthesis-and-biological-evaluation-of-1-benzylamino-2-hydroxyalkyl-derivatives-as-new-potential-disease-modifying-multifunctional-anti-alzheimer-s-agents
#4
Dawid Panek, Anna Więckowska, Jakub Jończyk, Justyna Godyń, Marek W Bajda, Tomasz Wichur, Anna Pasieka, Damijan Knez, Anja Pislar, Jan Korabecny, Ondrej Soukup, Vendula Sepsova, Raimon Sabaté, Janko Kos, Stanislav Gobec, Barbara Malawska
The multitarget approach is a promising paradigm in drug discovery, potentially leading to new treatment options for complex disorders, such as Alzheimer's disease. Herein, we present the discovery of a unique series of 1-benzylamino-2-hydroxyalkyl derivatives combining inhibitory activity against butyrylcholinesterase, β-secretase, β-amyloid and tau protein aggregation, all related to mechanisms which underpin Alzheimer's disease. Notably, diphenylpropylamine derivative 10 showed balanced activity against both disease-modifying targets - inhibition of β-secretase (IC50 hBACE-1 = 41...
January 18, 2018: ACS Chemical Neuroscience
https://www.readbyqxmd.com/read/29345419/targeting-bcl2-gene-promoter-g-quadruplex-with-a-new-class-of-furopyridazinone-based-molecules
#5
Jussara Amato, Alessia Pagano, Domenica Capasso, Sonia Di Gaetano, Mariateresa Giustiniano, Ettore Novellino, Antonio Randazzo, Bruno Pagano
Targeting of G-quadruplex-forming DNA in BCL2 gene promoter to inhibit the expression of anti-apoptotic Bcl-2 protein represents an attractive opportunity in cancer treatment. So far, efforts made in the discovery of molecules able to target BCL2 G-quadruplex mainly succeeded in the identification of ligands with poor drug-like properties. Here, a small series of furo[2,3-d]pyridazin-4(5H)-one derivatives were evaluated as a new class of drug-like G-quadruplex-targeting compounds. Biophysical studies showed that two derivatives could effectively bind to BCL2 G-quadruplex with good selectivity...
January 18, 2018: ChemMedChem
https://www.readbyqxmd.com/read/29344005/biological-clocks-their-relevance-to-immune-allergic-diseases
#6
REVIEW
Roberto Paganelli, Claudia Petrarca, Mario Di Gioacchino
The 2017 Nobel Prize for Physiology or Medicine, awarded for the discoveries made in the past 15 years on the genetic and molecular mechanisms regulating many physiological functions, has renewed the attention to the importance of circadian rhythms. These originate from a central pacemaker in the suprachiasmatic nucleus in the brain, photoentrained via direct connection with melanopsin containing, intrinsically light-sensitive retinal ganglion cells, and it projects to periphery, thus creating an inner circadian rhythm...
2018: Clinical and Molecular Allergy: CMA
https://www.readbyqxmd.com/read/29343841/microdosimetric-modeling-of-biological-effectiveness-for-boron-neutron-capture-therapy-considering-intra-and-intercellular-heterogeneity-in-10b-distribution
#7
Tatsuhiko Sato, Shin-Ichiro Masunaga, Hiroaki Kumada, Nobuyuki Hamada
We here propose a new model for estimating the biological effectiveness for boron neutron capture therapy (BNCT) considering intra- and intercellular heterogeneity in 10B distribution. The new model was developed from our previously established stochastic microdosimetric kinetic model that determines the surviving fraction of cells irradiated with any radiations. In the model, the probability density of the absorbed doses in microscopic scales is the fundamental physical index for characterizing the radiation fields...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343833/dopamine-d3-receptor-antagonist-reveals-a-cryptic-pocket-in-aminergic-gpcrs
#8
Noelia Ferruz, Stefan Doerr, Michelle A Vanase-Frawley, Yaozhong Zou, Xiaomin Chen, Eric S Marr, Robin T Nelson, Bethany L Kormos, Travis T Wager, Xinjun Hou, Anabella Villalobos, Simone Sciabola, Gianni De Fabritiis
The recent increase in the number of X-ray crystal structures of G-protein coupled receptors (GPCRs) has been enabling for structure-based drug design (SBDD) efforts. These structures have revealed that GPCRs are highly dynamic macromolecules whose function is dependent on their intrinsic flexibility. Unfortunately, the use of static structures to understand ligand binding can potentially be misleading, especially in systems with an inherently high degree of conformational flexibility. Here, we show that docking a set of dopamine D3 receptor compounds into the existing eticlopride-bound dopamine D3 receptor (D3R) X-ray crystal structure resulted in poses that were not consistent with results obtained from site-directed mutagenesis experiments...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29343694/sertraline-paroxetine-and-chlorpromazine-are-rapidly-acting-anthelmintic-drugs-capable-of-clinical-repurposing
#9
Janis C Weeks, William M Roberts, Caitlyn Leasure, Brian M Suzuki, Kristin J Robinson, Heather Currey, Phurpa Wangchuk, Ramon M Eichenberger, Aleen D Saxton, Thomas D Bird, Brian C Kraemer, Alex Loukas, John M Hawdon, Conor R Caffrey, Nicole F Liachko
Parasitic helminths infect over 1 billion people worldwide, while current treatments rely on a limited arsenal of drugs. To expedite drug discovery, we screened a small-molecule library of compounds with histories of use in human clinical trials for anthelmintic activity against the soil nematode Caenorhabditis elegans. From this screen, we found that the neuromodulatory drugs sertraline, paroxetine, and chlorpromazine kill C. elegans at multiple life stages including embryos, developing larvae and gravid adults...
January 17, 2018: Scientific Reports
https://www.readbyqxmd.com/read/29342835/small-peptides-able-to-suppress-prostaglandin-e%C3%A2-generation-in-renal-mesangial-cells
#10
Sofia Vasilakaki, Oleksandr Pastukhov, Thomas Mavromoustakos, Andrea Huwiler, George Kokotos
Peptide drug discovery may play a key role in the identification of novel medicinal agents. Here, we present the development of novel small peptides able to suppress the production of PGE₂ in mesangial cells. The new compounds were generated by structural alterations applied on GK115, a novel inhibitor of secreted phospholipase A₂, which has been previously shown to reduce PGE₂ synthesis in rat renal mesangial cells. Among the synthesized compounds, the tripeptide derivative 11 exhibited a nice dose-dependent suppression of PGE₂ production, similar to that observed for GK115...
January 13, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/29342186/doxorubicin-provoked-increase-of-mitotic-activity-and-concomitant-drain-of-g0-pool-in-therapy-resistant-be-2-c-neuroblastoma
#11
Isabell Hultman, Linnea Haeggblom, Ingvild Rognmo, Josefin Jansson Edqvist, Evelina Blomberg, Rouknuddin Ali, Lottie Phillips, Bengt Sandstedt, Per Kogner, Shahrzad Shirazi Fard, Lars Ährlund-Richter
In this study chemotherapy response in neuroblastoma (NB) was assessed for the first time in a transplantation model comprising non-malignant human embryonic microenvironment of pluripotent stem cell teratoma (PSCT) derived from diploid bona fide hESC. Two NB cell lines with known high-risk phenotypes; the multi-resistant BE(2)-C and the drug sensitive IMR-32, were transplanted to the PSCT model and the tumour growth was exposed to single or repeated treatments with doxorubicin, and thereafter evaluated for cell death, apoptosis, and proliferation...
2018: PloS One
https://www.readbyqxmd.com/read/29341934/advances-in-the-delivery-of-antisense-oligonucleotides-for-combating-bacterial-infectious-diseases
#12
REVIEW
Xiao-Yan Xue, Xing-Gang Mao, Ying Zhou, Zhou Chen, Yue Hu, Zheng Hou, Ming-Kai Li, Jing-Ru Meng, Xiao-Xing Luo
Discovery and development of new antibacterial drugs against multidrug resistant bacterial strains have become more and more urgent. Antisense oligonucleotides (ASOs) show immense potential to control the spread of resistant microbes due to its high specificity of action, little risk to human gene expression, and easy design and synthesis to target any possible gene. However, efficient delivery of ASOs to their action sites with enough concentration remains a major obstacle, which greatly hampers their clinical application...
January 13, 2018: Nanomedicine: Nanotechnology, Biology, and Medicine
https://www.readbyqxmd.com/read/29341586/development-of-a-novel-cytopathic-effect-based-phenotypic-screening-assay-against-cryptosporidium
#13
Alexander T Chao, Boon Heng Lee, Kah Fei Wan, Jeremy Selva, Bin Zou, Peter Gedeck, David Beer, Thierry T Diagana, Ghislain Bonamy, Ujjini H Manjunatha
Cryptosporidiosis is a diarrheal disease predominantly caused by Cryptosporidium parvum (Cp) and Cryptosporidium hominis (Ch), apicomplexan parasites which infect the intestinal epithelial cells of their human hosts. The only approved drug for cryptosporidiosis is nitazoxanide, which shows limited efficacy in immunocompromised children, the most vulnerable patient population. Thus, new therapeutics and in vitro infection models are urgently needed to address the current unmet medical need. Toward this aim, we have developed novel cytopathic effect (CPE)-based Cp and Ch assays in human colonic tumor (HCT-8) cells and compared them to traditional imaging formats...
January 17, 2018: ACS Infectious Diseases
https://www.readbyqxmd.com/read/29341142/evolutionary-and-genetic-features-of-drug-targets
#14
REVIEW
Yuan Quan, Zhong-Yi Wang, Xin-Yi Chu, Hong-Yu Zhang
In the modern drug discovery pipeline, identification of novel drug targets is a critical step. Despite rapid progress in developing biomedical techniques, it is still a great challenge to find promising new targets from the ample space of human genes. This fact is partially responsible for the situation of "more investments, fewer drugs" in the pharmaceutical industry. A series of recent researches revealed that successfully targeted genes share some common evolutionary and genetic features, which means that the knowledge accumulated in modern evolutionary biology and genetics is very helpful to identify potential drug targets and to find new drugs as well...
January 17, 2018: Medicinal Research Reviews
https://www.readbyqxmd.com/read/29341109/the-prescribable-drugs-with-efficacy-in-experimental-epilepsies-pde3-database-for-drug-repurposing-research-in-epilepsy
#15
Shayeeshan Sivapalarajah, Mathangi Krishnakumar, Harry Bickerstaffe, YikYing Chan, Joseph Clarkson, Alistair Hampden-Martin, Ahmad Mirza, Matthew Tanti, Anthony Marson, Munir Pirmohamed, Nasir Mirza
OBJECTIVE: Current antiepileptic drugs (AEDs) have several shortcomings. For example, they fail to control seizures in 30% of patients. Hence, there is a need to identify new AEDs. Drug repurposing is the discovery of new indications for approved drugs. This drug "recycling" offers the potential of significant savings in the time and cost of drug development. Many drugs licensed for other indications exhibit antiepileptic efficacy in animal models. Our aim was to create a database of "prescribable" drugs, approved for other conditions, with published evidence of efficacy in animal models of epilepsy, and to collate data that would assist in choosing the most promising candidates for drug repurposing...
January 17, 2018: Epilepsia
https://www.readbyqxmd.com/read/29339431/molecular-insights-into-function-and-competitive-inhibition-of-pseudomonas-aeruginosa-multiple-virulence-factor-regulator
#16
Tomoe Kitao, Francois Lepine, Seda Babloudi, Frederick Walte, Stefan Steinbacher, Klaus Maskos, Michael Blaesse, Michele Negri, Michael Pucci, Bob Zahler, Antonio Felici, Laurence G Rahme
New approaches to antimicrobial drug discovery are urgently needed to combat intractable infections caused by multidrug-resistant (MDR) bacteria. Multiple virulence factor regulator (MvfR or PqsR), a Pseudomonas aeruginosa quorum sensing transcription factor, regulates functions important in both acute and persistent infections. Recently identified non-ligand-based benzamine-benzimidazole (BB) inhibitors of MvfR suppress both acute and persistent P. aeruginosa infections in mice without perturbing bacterial growth...
January 16, 2018: MBio
https://www.readbyqxmd.com/read/29338446/the-latest-animal-models-of-ovarian-cancer-for-novel-drug-discovery
#17
Elizabeth Magnotti, Wayne A Marasco
Epithelial ovarian cancer is a heterogeneous disease classified into five subtypes, each with a different molecular profile. Most cases of ovarian cancer are diagnosed after metastasis of the primary tumor and are resistant to traditional platinum-based chemotherapeutics. Mouse models of ovarian cancer have been utilized to discern ovarian cancer tumorigenesis and the tumor's response to therapeutics. Areas covered: The authors provide a review of mouse models currently employed to understand ovarian cancer...
January 17, 2018: Expert Opinion on Drug Discovery
https://www.readbyqxmd.com/read/29338427/lipid-nanoparticles-for-intranasal-administration-application-to-nose-to-brain-delivery
#18
Luigi Battaglia, Pier Paolo Panciani, Elisabetta Muntoni, Maria Teresa Capucchio, Elena Biasibetti, Pasquale De Bonis, Silvia Mioletti, Marco Fontanella, Shankar Swaminathan
The blood brain barrier is a functional barrier allowing the entry into the brain of only essential nutrients, excluding other molecules. Its structure, although essential to keep the harmful entities out, is also a major roadblock for pharmacological treatment of brain diseases. Several alternative invasive drug delivery approaches, such as transcranial drug delivery and disruption of blood brain barrier have been explored, with limited success and several challenges. Intranasal delivery is a non-invasive methodology, which bypasses the systemic circulation, and, through the intra- and extra- neuronal pathways, provides direct brain drug delivery...
January 17, 2018: Expert Opinion on Drug Delivery
https://www.readbyqxmd.com/read/29338240/biki-life-sciences-a-new-suite-for-molecular-dynamics-and-related-methods-in-drug-discovery
#19
Sergio Decherchi, Giovanni Bottegoni, Andrea Spitaleri, Walter Rocchia, Andrea Cavalli
In this paper, we introduce the BiKi Life Sciences suite. This software makes it easy for computational medicinal chemists to run ad hoc molecular dynamics protocols in a novel and task-oriented environment; as a notebook, BiKi keeps memory of any activity together with dependencies among them. It offers unique accelerated protein-ligand binding/unbinding methods, and other useful tools to gain actionable knowledge from MD simulations and to simplify the drug discovery process.
January 17, 2018: Journal of Chemical Information and Modeling
https://www.readbyqxmd.com/read/29337200/mimicking-the-3d-biology-of-osteochondral-tissue-with-microfluidic-based-solutions-breakthroughs-towards-boosting-drug-testing-and-discovery
#20
REVIEW
Mariana R Carvalho, Rui Luís Reis, Joaquim Miguel Oliveira
The development of tissue-engineering (TE) solutions for osteochondral (OC) regeneration has been slowed by technical hurdles related to the recapitulation of their complex and hierarchical architecture. OC defects refer to damage of both the articular cartilage and the underlying subchondral bone. To repair an OC tissue defect, the complexity of the bone and cartilage must be considered. To help achieve this, microfluidics is converging with TE approaches to provide new treatment possibilities. Microfluidics uses precise micrometer-to-millimeter-scale fluid flows to achieve high-resolution and spatial and/or temporal control of the cell microenvironment, providing powerful tools for cell culturing...
January 11, 2018: Drug Discovery Today
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