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https://www.readbyqxmd.com/read/28231453/siderophore-transport-by-mmpl5-mmps5-protein-complex-in-mycobacterium-tuberculosis
#1
Padmani Sandhu, Yusuf Akhter
Iron is an essential metal ion required for the various physiological activities of bacteria. The pathogenic bacteria remain dependent on the host cell for their iron requirements and evolved with specialized scavenging machinery in the form of iron chelating siderophores. Mycobacterium tuberculosis has two types of siderophore molecules, mycobactin and carboxymycobactin. These are synthesized inside bacterial cells and need to be transported outside by specialized membrane associated proteins. MmpL5-MmpS5 (mycobacterial membrane protein large5-mycobacterial membrane protein small5) complex has been linked to the export of non-ferrated siderophores to extracellular environment but the precise molecular mechanism involved was largely unknown...
February 14, 2017: Journal of Inorganic Biochemistry
https://www.readbyqxmd.com/read/28231035/biologically-relevant-heterogeneity-metrics-and-practical-insights
#2
Albert Gough, Andrew M Stern, John Maier, Timothy Lezon, Tong-Ying Shun, Chakra Chennubhotla, Mark E Schurdak, Steven A Haney, D Lansing Taylor
Heterogeneity is a fundamental property of biological systems at all scales that must be addressed in a wide range of biomedical applications, including basic biomedical research, drug discovery, diagnostics, and the implementation of precision medicine. There are a number of published approaches to characterizing heterogeneity in cells in vitro and in tissue sections. However, there are no generally accepted approaches for the detection and quantitation of heterogeneity that can be applied in a relatively high-throughput workflow...
March 2017: SLAS Discov
https://www.readbyqxmd.com/read/28231034/upscaling-of-hips-cell-derived-neurons-for-high-throughput-screening
#3
Stefanie Traub, Heiko Stahl, Holger Rosenbrock, Eric Simon, Ralf Heilker
The advent of human-induced pluripotent stem (hiPS) cell-derived neurons promised to provide better model cells for drug discovery in the context of the central nervous system. This work demonstrates both the upscaling of cellular expansion and the acceleration of neuronal differentiation to accommodate the immense material needs of a high-throughput screening (HTS) approach. Using GRowth factor-driven expansion and INhibition of NotCH (GRINCH) during maturation, the derived cells are here referred to as GRINCH neurons...
March 2017: SLAS Discov
https://www.readbyqxmd.com/read/28230985/discovery-of-competitive-and-non-competitive-ligands-of-the-organic-cation-transporter-1-oct1-slc22a1
#4
Eugene C Chen, Natalia Khuri, Xiaomin Liang, Adrian Stecula, Huan-Chieh Chien, Sook Wah Yee, Yong Huang, Andrej Sali, Kathleen M Giacomini
Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here, we identified competitive and noncompetitive OCT1 interacting ligands in a library of 1,780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based a eukaryotic homolog. In parallel, high-throughput screening (HTS) was conducted using the fluorescent probe substrate ASP+ in cells overexpressing human OCT1...
February 23, 2017: Journal of Medicinal Chemistry
https://www.readbyqxmd.com/read/28230850/metal-and-additive-free-photoinduced-borylation-of-haloarenes
#5
Adelphe M Mfuh, Brett D Schneider, Westley Cruces, Oleg V Larionov
Boronic acids and esters have critical roles in the areas of synthetic organic chemistry, molecular sensors, materials science, drug discovery, and catalysis. Many of the current applications of boronic acids and esters require materials with very low levels of transition metal contamination. Most of the current methods for the synthesis of boronic acids, however, require transition metal catalysts and ligands that must be removed via additional purification procedures. This protocol describes a simple, metal- and additive-free method of conversion of haloarenes directly to boronic acids and esters...
March 2017: Nature Protocols
https://www.readbyqxmd.com/read/28230762/the-development-of-ck2-inhibitors-from-traditional-pharmacology-to-in-silico-rational-drug-design
#6
REVIEW
Giorgio Cozza
Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by "trial and error testing". In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range...
February 20, 2017: Pharmaceuticals
https://www.readbyqxmd.com/read/28229587/non-peptide-based-small-molecule-probe-for-fluorogenic-and-chromogenic-detection-of-chymotrypsin
#7
Lei Wu, Shu-Hou Yang, Hao Xiong, Jia-Qian Yang, Jun Guo, Wen-Chao Yang, Guang-Fu Yang
We report herein a non-peptide-based small molecule probe for fluorogenic and chromogenic detection of chymotrypsin, and the primary application. This probe was rationally designed by mimicking the peptide substrate and optimized by adjusting the recognization group. The refined probe 2 exhibits good specificity toward chymotrypsin, producing about 25-fold higher enhancement in both the fluorescence intensity and absorbance upon the catalysis by chymotrypsin. Compared with the most widely used peptide substrate (AMC-FPAA-Suc) of chymotrypsin, probe 2 shows about 5-fold higher binding affinity, and comparable catalytical efficiency against chymotrypsin...
February 23, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28229111/the-chronic-mild-stress-cms-model-of-depression-history-evaluation-and-usage
#8
REVIEW
Paul Willner
Now 30 years old, the chronic mild stress (CMS) model of depression has been used in >1300 published studies, with a year-on-year increase rising to >200 papers in 2015. Data from a survey of users show that while a variety of names are in use (chronic mild/unpredictable/varied stress), these describe essentially the same procedure. This paper provides an update on the validity and reliability of the CMS model, and reviews recent data on the neurobiological basis of CMS effects and the mechanisms of antidepressant action: the volume of this research may be unique in providing a comprehensive account of antidepressant action within a single model...
February 2017: Neurobiology of Stress
https://www.readbyqxmd.com/read/28228588/investigation-of-the-role-of-protein-kinase-d-in-human-rhinovirus-replication
#9
Anabel Guedán, Dawid Swieboda, Mark Charles, Marie Toussaint, Sebastian L Johnston, Amin Asfor, Anusha Panjwani, Tobias J Tuthill, Henry Danahay, Tony Raynham, Aurelie Mousnier, Roberto Solari
Picornavirus replication is known to cause extensive remodelling of Golgi and endoplasmic reticulum membranes and a number of the host proteins involved in the viral replication complex have been identified, including oxysterol binding protein (OSBP) and phosphatidylinositol 4-kinase III beta (PI4KB). Since both OSBP and PI4KB are substrates for protein kinase D (PKD) and PKD is known to be involved in the control of Golgi vesicular and lipid transport, we hypothesised that PKD played a role in viral replication...
February 22, 2017: Journal of Virology
https://www.readbyqxmd.com/read/28228082/recent-advances-in-protein-tyrosine-phosphatase-1b-targeted-drug-discovery-for-type-ii-diabetes-and-obesity
#10
Neelesh Maheswari, Chandrabose Karthikeyan, Piyush Trivedi, N S Hari Narayana Moorthy
Protein tyrosine phosphatase 1B (PTP1B) is an important therapeutic target for type II diabetes and obesity because of its pivotal role as a negative modulator in both insulin and leptin signalling pathways. Consequently, the discovery of PTP1B inhibitors has been the focus of researchers in both academia and pharmaceutical industry over the last two decades. Though, intense pharmaceutical research in this area has resulted in many potent PTP1B inhibitors, a vast majority of them possessed pTyr mimetic group such as phosphonates, carboxylic acids and sulphamic acids, which led to poor PTP1B selectivity and insufficient in vivo efficacy due to low cell permeability and bioavailability...
February 22, 2017: Current Drug Targets
https://www.readbyqxmd.com/read/28228080/marine-drugs-a-hidden-wealth-and-a-new-epoch-for-cancer-management
#11
Eram Shakeel, Deepika Arora, Qazi Mohammad Sajid Jamal, Salman Akhtar, Mohd Kalim Ahmad Khan, Mohammad A Kamal, Mohd Haris Siddiqui, Mohtashim Lohani, Jamal M Arif
Malignant tumors are the leading cause of death in humans. Due to tedious efforts and investigation made in the field of marine drug discovery, there is now a scientific bridge between marine and pharmaceutical sciences. However, at present only few marine drugs have been paved towards anticancer management, yet many more to be established. Marine organisms are profuse manufacturer of structurally inimitable bioactive metabolites that have unusual mechanisms of action and diverse biosynthetic pathways. Some of the compounds derived from marine organisms have antioxidant property and anticancer activities, but they are largely unexplored...
February 20, 2017: Current Drug Metabolism
https://www.readbyqxmd.com/read/28227815/lab-on-chips-for-manipulation-of-small-scale-organisms-to-facilitate-imaging-of-neurons-and-organs
#12
Ramtin Ardeshiri, Pouya Rezai, Ramtin Ardeshiri, Pouya Rezai, Ramtin Ardeshiri, Pouya Rezai
Caenorhabditis elegans (C. elegans) and Drosophila melanogaster (D. melanogaster) are widely-used model organisms for neurological and cardiac studies due to their simple neuronal (302 neurons in C. elegans) and cardiac (simple tubular organ in D. melanogaster) systems. However, their small sizes and continuous mobility impede their precise and timely manipulation, hence, limiting the assays that can be done using conventional manual methods. This has resulted in a need for technologies that allow multidirectional manipulation of model organisms to enable studies on target neurons and organs throughout the body...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28227433/microprinted-tumor-spheroids-enable-anti-cancer-drug-screening
#13
Pradip S Thakuri, Stephanie L Ham, Hossein Tavana, Pradip S Thakuri, Stephanie L Ham, Hossein Tavana, Stephanie L Ham, Hossein Tavana
Spheroids present a biologically relevant model of avascular tumors and a unique tool for discovery of anti-cancer drugs. Despite being used in research laboratories for several decades, spheroids are not routinely used for drug discovery primarily due to the difficulty of mass-producing uniformly-sized spheroids and intense labor involved in handling, drug treatment, and analyzing them. We overcome this barrier using a novel technology to robotically microprint spheroids in standard 384-well plates. An aqueous drop containing cancer cells is dispensed into a bath of a second, immiscible aqueous phase...
August 2016: Conference Proceedings: Annual International Conference of the IEEE Engineering in Medicine and Biology Society
https://www.readbyqxmd.com/read/28224391/development-and-evaluation-of-a-nanoemulsion-containing-ursolic-acid-a-promising-trypanocidal-agent-nanoemulsion-with-ursolic-acid-against-t-cruzi
#14
Erika Cristina Vargas de Oliveira, Zumira Aparecida Carneiro, Sérgio de Albuquerque, Juliana Maldonado Marchetti
Over a hundred years after the discovery of Chagas disease, this ailment continues to affect thousands of people. For more than 40 years, only two drugs have been available to treat it. Ursolic acid is a naturally occurring terpene that has shown a good trypanocidal action. However, the hydrophobicity of this compound presents a challenge for the development of proper delivery systems. Nanostructured systems are a prominent in delivering lipophilic drugs. Thus, a nanoemulsion containing ursolic acid was developed and had its trypanocidal activity and cytotoxicity evaluated...
February 21, 2017: AAPS PharmSciTech
https://www.readbyqxmd.com/read/28224120/oncolytic-virotherapy-including-rigvir-and-standard-therapies-in-malignant-melanoma
#15
REVIEW
Hani M Babiker, Irbaz Bin Riaz, Muhammad Husnain, Mitesh J Borad
The treatment of metastatic melanoma has evolved from an era where interferon and chemotherapy were the mainstay of treatments to an era where immunotherapy has become the frontline. Ipilimumab (IgG1 CTLA-4 inhibitor), nivolumab (IgG4 PD-1 inhibitor), pembrolizumab (IgG4 PD-1 inhibitor) and nivolumab combined with ipilimumab have become first-line therapies in patients with metastatic melanoma. In addition, the high prevalence of BRAF mutations in melanoma has led to the discovery and approval of targeted molecules, such as vemurafenib (BRAF kinase inhibitor) and trametinib (MEK inhibitor), as they yielded improved responses and survival in malignant melanoma patients...
2017: Oncolytic Virotherapy
https://www.readbyqxmd.com/read/28223231/the-impact-of-in-silico-screening-in-the-discovery-of-novel-and-safer-drug-candidates
#16
REVIEW
Didier Rognan
Drug discovery is a multidisciplinary and multivariate optimization endeavor. As such, in silico screening tools have gained considerable importance to archive, analyze and exploit the vast and ever-increasing amount of experimental data generated throughout the process. The current review will focus on the computer-aided prediction of the numerous properties that need to be controlled during the discovery of a preliminary hit and its promotion to a viable clinical candidate. It does not pretend to the almost impossible task of an exhaustive report but will highlight a few key points that need to be collectively addressed both by chemists and biologists to fuel the drug discovery pipeline with innovative and safe drug candidates...
February 13, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28223228/drug-discovery-using-induced-pluripotent-stem-cell-models-of-neurodegenerative-and-ocular-diseases
#17
REVIEW
Sandy S C Hung, Shahnaz Khan, Camden Y Lo, Alex W Hewitt, Raymond C B Wong
The revolution of induced pluripotent stem cell (iPSC) technology provides a platform for development of cell therapy, disease modeling and drug discovery. Recent technological advances now allow us to reprogram a patient's somatic cells into induced pluripotent stem cells (iPSCs). Together with methods to differentiate these iPSCs into the disease-relevant cell types, we are now able to model disease in vitro using iPSCs. Importantly, this represents a robust in vitro platform using patient-specific cells, providing opportunity for personalized precision medicine...
February 13, 2017: Pharmacology & Therapeutics
https://www.readbyqxmd.com/read/28223185/nanomedicine-as-a-potent-strategy-in-melanoma-tumor-microenvironment
#18
REVIEW
Vincent Pautu, Daniela Leonetti, Elise Lepeltier, Nicolas Clere, Catherine Passirani
Melanoma originated from melanocytes is the most aggressive type of skin cancer. Despite considerable progresses in clinical treatment with the discovery of BRAF or MEK inhibitors and monoclonal antibodies, the durability of response to treatment is often limited to the development of acquired resistance and systemic toxicity. The limited success of conventional treatment highlights the importance of understanding the role of melanoma tumor microenvironment in tumor developement and drug resistance. Nanoparticles represent a promising strategy for the development of new cancer treatments able to improve the bioavailability of drugs and increase their penetration by targeting specifically tumours cells and/or tumour environment...
February 18, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28223047/diversity-in-sequences-post-translational-modifications-and-expected-pharmacological-activities-of-toxins-from-four-conus-species-revealed-by-the-combination-of-cutting-edge-proteomics-transcriptomics-and-bioinformatics
#19
Michel Degueldre, Marion Verdenaud, Garikoitz Legarda, Rebeca Minambres, Sheila Zuniga, Mathieu Leblanc, Nicolas Gilles, Frederic Ducancel, Edwin De Pauw, Loic Quinton
Venomous animals have developed a huge arsenal of reticulated peptides for defense and predation. Based on various scaffolds, they represent a colossal pharmacological diversity, making them top candidates for the development of innovative drugs. Instead of relying on the classical, low-throughput bioassay-guided approach to identify innovative bioactive peptides, this work exploits a recent paradigm to access to venom diversity. This strategy bypasses the classical approach by combining high-throughput transcriptomics, proteomics and bioinformatics cutting-edge technologies to generate reliable peptide sequences...
February 18, 2017: Toxicon: Official Journal of the International Society on Toxinology
https://www.readbyqxmd.com/read/28222891/coumarins-scaffolds-as-cox-inhibitors
#20
REVIEW
Hrishikesh Mohan Revankar, Syed Nasir Abbas Bukhari, Gajjela Bharath Kumar, Hua-Li Qin
The discovery of COX enzymes has led to a better understanding of inflammation and its related biological pathways. Apart from being related to inflammation and pain, it has also been associated with cancer and neuropsychiatric diseases such as schizophrenia. Proverbially speaking, study of these enzymes has been crucial as they happen to "have fingers in many pies". Non-steroidal anti-inflammatory drugs (NSAID) that act specifically as COX-2 inhibitors have been known for a while; however these are also associated with severe side effects such as cardiac problems...
February 9, 2017: Bioorganic Chemistry
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