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https://www.readbyqxmd.com/read/28637123/inhibition-of-swarming-motility-of-pseudomonas-aeruginosa-by-methanol-extracts-of-alpinia-officinarum-hance-and-cinnamomum-tamala-t-nees-and-eberm
#1
Divya Lakshmanan, Jishudas Nanda, K Jeevaratnam
Bacterial drug resistance is a challenge in clinical settings, especially in countries like India. Hence, discovery of novel alternative therapeutics has become a necessity in the fight against drug resistance. Compounds that inhibit bacterial virulence properties form new therapeutic alternatives. Pseudomonas aeruginosa is an opportunistic, nosocomial pathogen that infects immune-compromised patients. Swarming motility is an important virulence property of Pseudomonas which aids it in reaching host cells under nutrient limiting conditions...
June 15, 2017: Natural Product Research
https://www.readbyqxmd.com/read/28637000/precision-medicine-for-hepatocellular-carcinoma-driver-mutations-and-targeted-therapy
#2
REVIEW
Xiao-Xiao Ding, Qing-Ge Zhu, Shi-Ming Zhang, Lei Guan, Ting Li, Lei Zhang, Shi-Yang Wang, Wan-Li Ren, Xue-Mei Chen, Jing Zhao, Song Lin, Zhi-Zhen Liu, Yan-Xia Bai, Bing He, Hu-Qin Zhang
Hepatocellular carcinoma (HCC) is the third most frequent cause of tumor-related mortality and there are an estimated approximately 850,000 new cases annually. Most HCC patients are diagnosed at middle or advanced stage, losing the opportunity of surgery. The development of HCC is promoted by accumulated diverse genetic mutations, which confer selective growth advantages to tumor cells and are called "driver mutations". The discovery of driver mutations provides a novel precision medicine strategy for late stage HCC, called targeted therapy...
June 6, 2017: Oncotarget
https://www.readbyqxmd.com/read/28636912/channeling-of-camp-in-pde-pka-complexes-promotes-signal-adaptation
#3
Nikhil Kumar Tulsian, Srinath Krishnamurthy, Ganesh Srinivasan Anand
Spatiotemporal control of the cAMP signaling pathway is governed by both hormonal stimulation of cAMP generation by adenylyl cyclases (activation phase) and cAMP hydrolysis by phosphodiesterases (PDEs) (termination phase). The termination phase is initiated by PDEs actively targeting the protein kinase A (PKA) R-subunit through formation of a PDE-PKAR-cyclic adenosine monophosphate (cAMP) complex (the termination complex). Our results using PDE8 as a model PDE, reveal that PDEs mediate active hydrolysis of cAMP bound to its receptor RIα by enhancing the enzymatic activity...
June 20, 2017: Biophysical Journal
https://www.readbyqxmd.com/read/28636884/major-achievements-of-evidence-based-traditional-chinese-medicine-in-treating-major-diseases
#4
REVIEW
Jung Chao, Yuntao Dai, Robert Verpoorte, Wing Lam, Yung-Chi Cheng, Li-Heng Pao, Wei Zhang, Shilin Chen
A long history of use and extensive documentation of the clinical practices of traditional Chinese medicine resulted in a considerable number of classical preparations, which are still widely used. This heritage of our ancestors provides a unique resource for drug discovery. Already, a number of important drugs have been developed from traditional medicines, which in fact form the core of Western pharmacotherapy. Therefore, this article discusses the differences in drug development between traditional medicine and Western medicine...
June 18, 2017: Biochemical Pharmacology
https://www.readbyqxmd.com/read/28636781/discovery-of-two-bombinin-peptides-with-antimicrobial-and-anticancer-activities-from-the-skin-secretion-of-oriental-fire-bellied-toad-bombina-orientalis
#5
Chang Zhou, Zhengming Wang, Xin Peng, Yao Liu, Yangjun Lin, Zhe Zhang, Yuling Qiu, Meihua Jin, Ran Wang, Dexin Kong
Amphibian skin secretions are known to contain numerous peptides with a large array of biological activities. Bombinins are a group of amphibian derived peptides with broad spectrum antimicrobial activities that have been only identified from the ancient toad species, Bombina. In this study, we described the identification and characterization of a novel bombinin precursor which encoded a bombinin like peptide (BLP-7) and a novel bombinin H type peptide (named as Bombinin H-BO) from the skin secretion of Oriental fire-bellied toad, Bombina orientalis...
June 21, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28636311/insights-into-integrated-lead-generation-and-target-identification-in-malaria-and-tuberculosis-drug-discovery
#6
John Okombo, Kelly Chibale
New, safe and effective drugs are urgently needed to treat and control malaria and tuberculosis, which affect millions of people annually. However, financial return on investment in the poor settings where these diseases are mostly prevalent is very minimal to support market-driven drug discovery and development. Moreover, the imminent loss of therapeutic lifespan of existing therapies due to evolution and spread of drug resistance further compounds the urgency to identify novel effective drugs. However, the advent of new public-private partnerships focused on tropical diseases and the recent release of large data sets by pharmaceutical companies on antimalarial and antituberculosis compounds derived from phenotypic whole cell high throughput screening have spurred renewed interest and opened new frontiers in malaria and tuberculosis drug discovery...
June 21, 2017: Accounts of Chemical Research
https://www.readbyqxmd.com/read/28636189/discovery-of-alkyl-bis-oxy-dibenzimidamide-derivatives-as-novel-protein-arginine-methyltransferase-1-prmt1-inhibitors
#7
Wei-Yao Zhang, Wen-Chao Lu, Hao Jiang, Zheng-Bing Lv, Yi-Qian Xie, Fu-Lin Lian, Zhong-Jie Liang, Yu-Xi Jiang, Da-Jin Wang, Cheng Luo, Jia Jin, Fei Ye
Protein arginine methylation, a post-translational modification critical for a variety of biological processes, is catalyzed by protein arginine N-methyltransferases (PRMTs). In particular, PRMT1 is responsible for over 85% of the arginine methylation in mammalian cells. Dysregulation of PRMT1 is involved in diverse pathological diseases including cancers. However, most current PRMT1inhibitors are lack of specificity, efficacy, and bioavailability. Herein, a series of alkyl bis(oxy)dibenzimidamide derivatives were identified as selective PRMT1 inhibitors...
June 21, 2017: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/28635674/exploring-wound-healing-genomic-machinery-with-a-network-based-approach
#8
Francesca Vitali, Simone Marini, Martina Balli, Hanne Grosemans, Maurilio Sampaolesi, Yves A Lussier, Maria Gabriella Cusella De Angelis, Riccardo Bellazzi
The molecular mechanisms underlying tissue regeneration and wound healing are still poorly understood despite their importance. In this paper we develop a bioinformatics approach, combining biology and network theory to drive experiments for better understanding the genetic underpinnings of wound healing mechanisms and for selecting potential drug targets. We start by selecting literature-relevant genes in murine wound healing, and inferring from them a Protein-Protein Interaction (PPI) network. Then, we analyze the network to rank wound healing-related genes according to their topological properties...
June 21, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28635653/virtual-screening-against-phosphoglycerate-kinase-1-in-quest-of-novel-apoptosis-inhibitors
#9
Jie Xia, Bo Feng, Qianhang Shao, Yuhe Yuan, Xiang Simon Wang, Naihong Chen, Song Wu
Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson's disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents...
June 21, 2017: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
https://www.readbyqxmd.com/read/28635544/heparin-new-life-for-an-old-drug
#10
Carlos Raúl Aláez-Versón, Elena Lantero, Xavier Fernàndez-Busquets
Heparin is one of the oldest drugs, which nevertheless remains in widespread clinical use as an inhibitor of blood coagulation. The history of its identification a century ago unfolded amid one of the most fascinating scientific controversies turning around the distribution of credit for its discovery. The composition, purification and structure-function relationship of this naturally occurring glycosaminoglycan regarding its classical role as anticoagulant will be dealt with before proceeding to discuss its therapeutic potential in, among other, inflammatory and infectious disease, cancer treatment, cystic fibrosis and Alzheimer's disease...
June 21, 2017: Nanomedicine
https://www.readbyqxmd.com/read/28634393/a-small-molecule-ds44170716-inhibits-ca-2-induced-mitochondrial-permeability-transition
#11
Naohiro Kon, Atsushi Satoh, Naoki Miyoshi
Mitochondria are involved in a variety of physiological and pathological processes. Ca(2+) uptake is one of the important functions of the organelle for maintenance of cellular Ca(2+) homeostasis. In pathological conditions such as ischemia reperfusion injury, Ca(2+) overload into mitochondria induces mitochondrial permeability transition (MPT), a critical step for cell death. Because inhibition of MPT is a promising approach to protecting cells and organs, it is important for drug discovery to identify novel chemicals or mechanisms to inhibit MPT...
June 20, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28634338/coumarin-benzimidazole-hybrids-as-a-potent-antimicrobial-agent-synthesis-and-biological-elevation
#12
L Ravithej Singh, Srinivasa Rao Avula, Sneha Raj, Akanksha Srivastava, Gopala Reddy Palnati, C K M Tripathi, Mukesh Pasupuleti, Koneni V Sashidhara
Molecular hybridization approach is an emerging tool in drug discovery for designing new pharmacophores with biological activity. A novel, new series of coumarin-benzimidazole hybrids were designed, synthesized and evaluated for their broad spectrum antimicrobial activity. Among all the synthesized molecules, compound (E)-3-(2-1H-benzo[d]imidazol-1-yl)-1-((4-chlorobenzyl)oxy)imino)ethyl)-2H-chromen-2-one showed the most promising broad spectrum antibacterial activity against Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis and Proteus vulgaris...
June 21, 2017: Journal of Antibiotics
https://www.readbyqxmd.com/read/28634268/30-years-of-the-mineralocorticoid-receptor-mineralocorticoid-receptor-antagonists-60-years-of-research-and-development
#13
REVIEW
Peter Kolkhof, Lars Bärfacker
The cDNA of the mineralocorticoid receptor (MR) was cloned 30 years ago, in 1987. At that time, spirolactone, the first generation of synthetic steroid-based MR antagonists (MRAs), which was identified in preclinical in vivo models, had already been in clinical use for 30 years. Subsequent decades of research and development by Searle & Co., Ciba-Geigy, Roussel Uclaf and Schering AG toward identifying a second generation of much more specific steroidal MRAs were all based on the initial 17-spirolactone construct...
July 2017: Journal of Endocrinology
https://www.readbyqxmd.com/read/28633899/discovery-of-bms-961955-an-allosteric-inhibitor-of-the-hepatitis-c-virus-ns5b-polymerase
#14
Barbara Zhizhen Zheng, Stanley V D'Andrea, Umesh Hanumegowda, Jay O Knipe, Kathy Mosure, Xiaoliang Zhuo, Julie A Lemm, Mengping Liu, Karen L Rigat, Ying-Kai Wang, Hua Fang, Chris Poronsky, Jingfang Cutrone, Dauh-Rurng Wu, Pirama Nayagam Arunachalam, T J Balapragalathan, Arunachalam Arumugam, Arvind Mathur, Nicholas A Meanwell, Min Gao, Susan B Roberts, John F Kadow
The synthesis, structure-activity relationship (SAR) data, and further optimization of the metabolic stability and pharmacokinetic (PK) properties for a previously disclosed class of cyclopropyl-fused indolobenzazepine HCV NS5B polymerase inhibitors are described. These efforts led to the discovery of BMS-961955 as a viable contingency backup to beclabuvir which was recently approved in Japan for the treatment of HCV as part of a three drug, single pill combination marketed as Ximency(TM).
June 11, 2017: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28632991/uncovering-the-repertoire-of-fungal-secondary-metabolites-from-fleming-s-lab-to-the-international-space-station
#15
Tomasz Boruta
Fungi produce a variety of secondary metabolites (SMs), low-molecular weight compounds associated with many potentially useful biological activities. The examples of biotechnologically relevant fungal metabolites include penicillin, a beta-lactam antibiotic, and lovastatin, a cholesterol-lowering drug. The discovery of pharmaceutical lead compounds within the microbial metabolic pools relies on the selection and biochemical characterization of promising strains. Not all SMs are produced under standard cultivation conditions, hence the uncovering of chemical potential of investigated strains often requires the use of induction strategies to awake the associated biosynthetic genes...
June 20, 2017: Bioengineered
https://www.readbyqxmd.com/read/28632924/metabolomics-as-a-driver-in-advancing-precision-medicine-in-sepsis
#16
Michelle Eckerle, Lilliam Ambroggio, Michael Puskarich, Brent Winston, Alan E Jones, Theodore J Standiford, Kathleen A Stringer
OBJECTIVE: The objective of this review is to explain the science of metabolomics-a science of systems biology that measures and studies endogenous small molecules (metabolites) that are present in a single biological sample-and its application to the diagnosis and treatment of sepsis. In addition, we discuss how discovery through metabolomics can contribute to the development of precision medicine targets for this complex disease state and the potential avenues for those new discoveries to be applied in the clinical environment...
June 20, 2017: Pharmacotherapy
https://www.readbyqxmd.com/read/28632820/the-nexus-of-stem-cell-derived-beta-cells-and-genome-engineering
#17
Sara D Sackett, Aida Rodriguez, Jon S Odorico
Diabetes, type 1 and type 2 (T1D and T2D), are diseases of epidemic proportions, which are complicated and defined by genetics, epigenetics, environment, and lifestyle choices. Current therapies consist of whole pancreas or islet transplantation. However, these approaches require life-time immunosuppression, and are compounded by the paucity of available donors. Pluripotent stem cells have advanced research in the fields of stem cell biology, drug development, disease modeling, and regenerative medicine, and importantly allows for the interrogation of therapeutic interventions...
2017: Review of Diabetic Studies: RDS
https://www.readbyqxmd.com/read/28632448/neuroregeneration-versus-neurodegeneration-toward-a-paradigm-shift-in-alzheimer-s-disease-drug-discovery
#18
Elisa Uliassi, Annachiara Gandini, Rosaria Carmela Perone, Maria Laura Bolognesi
Alzheimer's disease represents an enormous global burden in terms of human suffering and economic cost. To tackle the current lack of effective drugs and the continuous clinical trial failures might require a shift from the prevailing paradigm targeting pathogenesis to the one targeting neural stem cells (NSCs) regeneration. In this context, small molecules have come to the forefront for their potential to manipulate NSCs, provide therapeutic tools and unveil NSCs biology. Classically, these molecules have been generated either by target-based or phenotypic approaches...
June 20, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28632406/tailored-pharmacophore-model-to-enhance-virtual-screening-and-drug-discovery-a-case-study-on-the-identification-of-potential-inhibitors-against-drug-resistant-mycobacterium-tuberculosis-3r-hydroxyacyl-acp-dehydratases
#19
Kgothatso E Machaba, Ndumiso N Mhlongo, Yussif M Dokurugu, Mahmoud Es Soliman
AIM: Virtual screening (VS) is powerful tool in discovering molecular inhibitors that are most likely to bind to drug targets of interest. Herein, we introduce a novel VS approach, so-called 'tailored-pharmacophore', in order to explore inhibitors that overcome drug resistance. Methodology & results: The emergence and spread of drug resistance strains of tuberculosis is one of the most critical issues in healthcare. A tailored-pharmacophore approach was found promising to identify in silico predicted hit with better binding affinities in case of the resistance mutations in MtbHadAB as compared with thiacetazone, a prodrug used in the clinical treatment of tuberculosis...
June 20, 2017: Future Medicinal Chemistry
https://www.readbyqxmd.com/read/28632338/difluoromethylation-reactions-of-organic-compounds
#20
Damian E Yerien, Sebastian Barata-Vallejo, Al Postigo
The relevance of the -CF2H moiety has attracted considerable attention from organic synthetic and medicinal chemistry communities, because this group can act as a more lipophilic isostere of the carbinol, thiol, hydroxamic acid or amide groups. Being weakly acidic, the CF2H moiety can establish hydrogen bonding interactions to improve the binding selectivity of biologically active compounds. Therefore, the hydroxyl, amino, and thio substituents of lead structures are routinely replaced by a CF2H motif in drug discovery, with great benefits in the pharmacological activity of drugs and drug candidates and agrochemicals...
June 20, 2017: Chemistry: a European Journal
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