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https://read.qxmd.com/read/30786217/kinetics-of-drug-binding-and-residence-time
#1
Mattia Bernetti, Matteo Masetti, Walter Rocchia, Andrea Cavalli
The kinetics of drug binding and unbinding is assuming an increasingly crucial role in the long, costly process of bringing a new medicine to patients. For example, the time a drug spends in contact with its biological target is known as residence time (the inverse of the kinetic constant of the drug-target unbinding, 1/ koff ). Recent reports suggest that residence time could predict drug efficacy in vivo, perhaps even more effectively than conventional thermodynamic parameters (free energy, enthalpy, entropy)...
February 20, 2019: Annual Review of Physical Chemistry
https://read.qxmd.com/read/30786178/duckcov-a-dynamic-undocking-based-virtual-screening-protocol-for-covalent-binders
#2
Moira Rachman, Andrea Scarpino, Dávid Bajusz, Gyula Palfy, Istvan Vida, Andras Perczel, Xavier Barril, György M Keseru
Thanks to recent guidelines, the design of safe and effective covalent drugs has gained significant interest. Other than targeting non-conserved nucleophilic residues, optimizing the non-covalent binding framework is important to improve potency and selectivity of covalent binders towards the desired target. Strong efforts have been made in extending the computational toolkits to include a covalent mechanism of protein targeting, like in the development of covalent docking methods for binding mode prediction...
February 20, 2019: ChemMedChem
https://read.qxmd.com/read/30786171/drug-discovery-for-pemphigoid-diseases
#3
Anika Kasprick, Katja Bieber, Ralf J Ludwig
Pemphigoid diseases (PDs) are a group of autoimmune bullous diseases characterized and caused by autoantibodies targeting structural proteins of the skin and mucous membranes. Chronic inflammation, subepidermal blistering, and often scaring are the clinical characteristics of PDs. Itching and, in severe cases, disabilities resulting from scaring (i.e., blindness, esophageal strictures) are the leading subjective symptoms. Treatment of PDs, which is based on nonspecific immunosuppression, is challenging because of frequent relapses, lack of efficacy, and numerous adverse events...
February 20, 2019: Current Protocols in Pharmacology
https://read.qxmd.com/read/30786091/coordinating-tissue-regeneration-through-tgf-%C3%AE-activated-kinase-1-tak1-in-activation-and-re-activation
#4
Hsiao Hsin Sung Hsieh, Shailesh Agarwal, David J Cholok, Shawn J Loder, Kieko Kaneko, Amanda Huber, Michael T Chung, Kavitha Ranganathan, Joe Habbouche, John Li, Jonathan Butts, Jonathan Reimer, Arminder Kaura, James Drake, Christopher Breuler, Caitlin R Priest, Joe Nguyen, Cameron Brownley, Jonathan Peterson, Serra Ucer Ozgurel, Yashar S Niknafs, Shuli Li, Maiko Inagaki, Greg Scott, Paul Krebsbach, Michael T Longaker, Kenneth Westover, Nathanael Gray, Jun Ninomiya-Tsuji, Yuji Mishina, Benjamin Levi
Aberrant wound healing presents as inappropriate or insufficient tissue formation. Using a model of musculoskeletal injury, we demonstrate that loss of TGF-β activated kinase 1 (TAK1) signaling reduces inappropriate tissue formation (heterotopic ossification) through reduced cellular differentiation. Upon identifying increased proliferation with loss of TAK1 signaling, we considered a regenerative approach to address insufficient tissue production through coordinated inactivation of TAK1 to promote cellular proliferation, followed by re-activation to elicit differentiation and extracellular matrix (ECM) production...
February 20, 2019: Stem Cells
https://read.qxmd.com/read/30785286/synthesis-of-rosmarinic-acid-amides-as-antioxidative-and-hypoglycemic-agents
#5
Nunzio Cardullo, Giorgia Catinella, Giuseppe Floresta, Vera Muccilli, Sergio Rosselli, Antonio Rescifina, Maurizio Bruno, Corrado Tringali
Type 2 diabetes mellitus (T2DM) is an important metabolic disorder for which there is an urgent need for new antidiabetic drugs. α-Glucosidase inhibition is an established protocol for T2DM therapy. Because hyperglycemia causes oxidative tissue damage, the development of agents with both α-glucosidase inhibition and antioxidant activity from natural or natural-derived polyphenols such derivatives of rosmarinic acid (RA) represents an attractive therapeutic option. We report a study on amides 1-10 derived from RA and their evaluation for yeast α-glucosidase inhibition and antioxidant activity (DPPH and ORAC tests)...
February 20, 2019: Journal of Natural Products
https://read.qxmd.com/read/30784888/application-of-an-hplc-ms-ms-method-for-teicoplanin-drug-substance-and-related-impurities-part-2-identity-assignment-of-related-impurities
#6
Sara Tengattini, Federica Corana, Davide Bianchi, Giorgio Marrubini, Raffaella Colombo, Sandra Furlanetto, Marco Terreni, Caterina Temporini
A liquid chromatographic MS-compatible method was applied to the structural elucidation of Teicoplanin for identification CRS components. The method, previously developed by our group, involves the use of LiChrospher 100 RP-18 column with a mobile phase composed of ammonium formate 25 mM at pH 6.00 and acetonitrile (ACN). All the peaks with a 0.10% UV area, largely above the disregard limit of 0.15% as fixed by EMA, were considered and submitted to MS/MS fragmentation experiments. The study of MS/MS spectrum collected for Teicoplanin complex major component (namely A2-2 ) allowed to elucidate the fragmentation pathway and enabled the successful identity assignment of all the 42 detected species...
February 13, 2019: Journal of Pharmaceutical and Biomedical Analysis
https://read.qxmd.com/read/30784877/a-fragment-based-approach-towards-the-discovery-of-n-substituted-tropinones-as-inhibitors-of-mycobacterium-tuberculosis-transcriptional-regulator-ethr2
#7
Hugues Prevet, Martin Moune, Abdalkarim Tanina, Christian Kemmer, Adrien Herledan, Rosangela Frita, Alexandre Wohlkönig, Marilyne Bourotte, Baptiste Villemagne, Florence Leroux, Marc Gitzinger, Alain R Baulard, Benoit Déprez, René Wintjens, Nicolas Willand, Marion Flipo
Tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis, represents one of the most challenging threat to public health worldwide, and with the increasing resistance to approved TB drugs, it is needed to develop new strategies to address this issue. Ethionamide is one of the most widely used drugs for the treatment of multidrug-resistant TB. It is a prodrug that requires activation by mycobacterial monooxygenases to inhibit the enoyl-ACP reductase InhA, which is involved in mycolic acid biosynthesis...
February 10, 2019: European Journal of Medicinal Chemistry
https://read.qxmd.com/read/30784750/the-detection-of-drugs-of-abuse-and-pharmaceuticals-in-drinking-water-using-solid-phase-extraction-and-liquid-chromatography-mass-spectrometry
#8
Yan Peng, Lata Gautam, Sarah W Hall
Pharmaceuticals and drugs of abuse including novel psychoactive substances (NPS) are emerging as newer contaminants in the aquatic environment. The presence of such pollutants has implications on the environment as well as public health and therefore their identification is important when monitoring water quality. This research presents a new method for the simultaneous detection of 20 drugs of abuse and pharmaceuticals in drinking water, including 15 NPS, three traditional illicit drugs and two antidepressants...
February 14, 2019: Chemosphere
https://read.qxmd.com/read/30784310/design-and-synthesis-of-novel-7-n-substituted-thioureidopiperazinyl-methyl-camptothecin-derivatives-as-potential-cytotoxic-agents
#9
Zi-Long Song, Guan-Zhou Yang, Jun-Cai Li, Ying-Qian Liu, Chen-Jie Yang, Masuo Goto, Zhi-Jun Zhang, Susan L Morris-Natschke, Hua Liu, Kuo-Hsiung Lee
As part of continuing our research on diverse C-7 derivatives of camptothecin (CPT), 16 CPT derivatives bearing piperazinyl-thiourea chemical scaffold and different substituent groups have been designed, synthesized and evaluated in vitro for cytotoxicity against five tumor cell lines (A-549, MDA-MB-231, MCF-7, KB and KBvin). As a result, all the synthesized compounds showed promising in vitro cytotoxic activity against the five tumor cell lines tested, and were more potent than irinotecan. Importantly, compounds 13 g (IC50 = 0...
February 20, 2019: Natural Product Research
https://read.qxmd.com/read/30784204/method-validation-and-preliminary-pharmacokinetic-studies-on-the-new-designer-stimulant-3-fluorophenmetrazine-3-fpm
#10
Christina Grumann, Laura M Huppertz, Philippe Bisel, Verena Angerer, Volker Auwärter
Pharmaceutical research not only provides the basis for the development of new medicinal products but also for the synthesis of new drugs of abuse. 3-Fluorophenmetrazine (3-FPM), a fluorinated derivative of the anorectic phenmetrazine, was first patented in 2011 and appeared on the drug market in 2014. Though invented for potential medical purposes, pharmacokinetic data on this compound, crucial for interpreting forensic as well as clinical cases, are not available. Therefore, a liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS) method for the detection of 3-FPM in serum, urine and oral fluid was developed, validated for urine and serum, and used to quantify 3-FPM in samples obtained during a controlled self-experiment...
February 19, 2019: Drug Testing and Analysis
https://read.qxmd.com/read/30784084/the-preparation-and-investigation-of-spinosin-phospholipid-complex-self-microemulsifying-drug-delivery-system-based-on-the-absorption-characteristics-of-spinosin
#11
Panpan Song, Changjiangsheng Lai, Junbo Xie, Yanqing Zhang
OBJECTIVES: The aim of this research was to investigate the intestinal absorption characteristics and mechanisms of spinosin (SPI), and a new dosage form was prepared to increase the intestinal absorption of SPI. METHODS: In this study, the intestinal absorption characteristics and mechanisms of SPI were first investigated using in situ absorption model and Caco-2 monolayer model. Subsequently, the phospholipid complex (PLC) loaded with SPI was prepared followed by a self-microemulsifying drug delivery system (SMEDDS) technique for developing a more efficient formulation...
February 19, 2019: Journal of Pharmacy and Pharmacology
https://read.qxmd.com/read/30784076/snx9-determines-the-surface-levels-of-integrin-%C3%AE-1-in-vascular-endothelial-cells-implication-in-poor-prognosis-of-human-colorectal-cancers-overexpressing-snx9
#12
Kazufumi Tanigawa, Masashi Maekawa, Takeshi Kiyoi, Jun Nakayama, Riko Kitazawa, Sohei Kitazawa, Kentaro Semba, Tomohiko Taguchi, Satoshi Akita, Motohira Yoshida, Kei Ishimaru, Yuji Watanabe, Shigeki Higashiyama
Angiogenesis, the formation of new blood vessels, is involved in a variety of diseases including the tumor growth. In response to various angiogenic stimulations, a number of proteins on the surface of vascular endothelial cells are activated to coordinate cell proliferation, migration, and spreading processes to form new blood vessels. Plasma membrane localization of these angiogenic proteins, which include vascular endothelial growth factor receptors and integrins, are warranted by intracellular membrane trafficking...
February 19, 2019: Journal of Cellular Physiology
https://read.qxmd.com/read/30783904/delivery-technologies-for-orally-inhaled-products-an-update
#13
Chaeho Moon, Hugh D C Smyth, Alan B Watts, Robert O Williams
Orally inhaled products have well-known benefits. They allow for effective local administration of many drugs for the treatment of pulmonary disease, and they allow for rapid absorption and avoidance of first-pass metabolism of several systemically acting drugs. Several challenges remain, however, such as dosing limitations, low and variable deposition of the drug in the lungs, and high drug deposition in the oropharynx region. These challenges have stimulated the development of new delivery technologies. Both formulation improvements and new device technologies have been developed through an improved understanding of the mechanisms of aerosolization and lung deposition...
February 19, 2019: AAPS PharmSciTech
https://read.qxmd.com/read/30783717/new-arylpiperazine-derivatives-with-antidepressant-like-activity-containing-isonicotinic-and-picolinic-nuclei-evidence-for-serotonergic-system-involvement
#14
Ewa Kędzierska, Ferdinando Fiorino, Elisa Magli, Ewa Poleszak, Piotr Wlaź, Jolanta Orzelska-Górka, Bartosz Knap, Jolanta H Kotlińska
Therapy of depression is difficult and still insufficient despite the presence of many antidepressants on the market. Therefore, there is a constant need to search for new, safer, and more effective drugs that could be used in the treatment of depression. Among many methods, chemical modification is an important strategy for new drug development. This study evaluates antidepressant-like effects and possible mechanism of action of two new arylpiperazine derivatives with isonicotinic and picolinic nuclei, compounds 4pN-(3-(4-(piperonyl)piperazin-1-yl)propyl) isonicotinamide and 3oN-(2-(4-(pyrimidin-2-yl)piperazin-1-yl)ethyl) picolinamide...
February 19, 2019: Naunyn-Schmiedeberg's Archives of Pharmacology
https://read.qxmd.com/read/30783546/new-european-union-regulations-related-to-whole-slide-image-scanners-and-image-analysis-software
#15
EDITORIAL
Marcial García-Rojo, David De Mena, Pedro Muriel-Cueto, Lidia Atienza-Cuevas, Manuel Domínguez-Gómez, Gloria Bueno
Whole slide imaging (WSI) scanners and automatic image analysis algorithms, in order to be used for clinical applications, including primary diagnosis in pathology, are subject to specific regulatory frameworks in each country. Until May 25, 2018, in the European Union (EU), in vitro diagnostic (IVD) medical devices were regulated by directive 98/79/EC ( in vitro diagnostic medical device directive [IVDD]). Main scanner vendors have obtained a Conformité Européenne mark of their products that in Europe were classified as General Class IVDD, so that conformity is only based on a self-declaration of the manufacturer...
2019: Journal of Pathology Informatics
https://read.qxmd.com/read/30783515/enhanced-phosphatidylserine-selective-cancer-therapy-with-irradiation-and-sapc-dops-nanovesicles
#16
Harold W Davis, Subrahmanya D Vallabhapurapu, Zhengtao Chu, Swarajya L Vallabhapurapu, Robert S Franco, Michelle Mierzwa, William Kassing, William L Barrett, Xiaoyang Qi
Normal living cells exhibit phosphatidylserine (PS) primarily within the intracellular leaflet of the plasma membrane. In contrast, viable cancer cells have high levels of PS on the external surface, and exhibit a broad range of surface PS, even within specific types of cancer. Agents that target surface PS have recently been developed to treat tumors and are expected to be more effective with higher surface PS levels. In this context, we examined whether surface PS is increased with irradiation. In vitro irradiation of cancer cell lines selected surviving cells that had higher surface PS in a dose- and time-dependent manner...
January 25, 2019: Oncotarget
https://read.qxmd.com/read/30783503/aryl-substituted-benzimidazolones-as-potent-hiv-1-non-nucleoside-reverse-transcriptase-inhibitors
#17
Nicole Pribut, Adriaan E Basson, Willem A L van Otterlo, Dennis C Liotta, Stephen C Pelly
Since the discovery of HIV as the etiological agent of AIDS, the virus has infected millions of people each year. Fortunately, with the use of HAART, viremia can be suppressed to below detectable levels in the infected individuals, which significantly improves their quality of life and prevents the onset of AIDS. However, HAART is not curative and issues relating to adherence and drug resistance may lead to the re-emergence of viremia, the development of AIDS, and ultimately death. To address a pressing need for the development of new and efficacious antiretroviral agents with activity against viruses bearing prevalent resistant mutations, we have designed two generations of benzimidazolone derivatives as HIV non-nucleoside reverse transcriptase inhibitors...
February 14, 2019: ACS Medicinal Chemistry Letters
https://read.qxmd.com/read/30783497/tissue-imaging-by-mass-spectrometry-a-practical-guide-for-the-medicinal-chemist
#18
Robert W Johnson, Nari Talaty
Understanding the tissue distribution of therapeutic molecules is often critical for assessing their efficacy and toxicity. Unfortunately, standard methods for monitoring localized drug distribution are resource-intensive and are typically performed late in the discovery process. As a result, early development efforts often progress without detailed information on the effect that changes in structure and/or formulation have on drug localization. Recent innovations in mass spectrometry (MS) provide new options for mapping the spatial distribution of drug in tissue and allow parallel detection of endogenous species...
February 14, 2019: ACS Medicinal Chemistry Letters
https://read.qxmd.com/read/30783496/evolution-of-small-molecule-kinase-drugs
#19
Helen L Lightfoot, Frederick W Goldberg, Joerg Sedelmeier
The development of small molecule kinase drugs is a rapidly evolving field and represents one of the most important research areas within oncology. This innovation letter provides an overview and analysis of approved kinase drugs according to their WHO registration (INN) dates, primary biological targets, and selectivity and structural similarities, which are also depicted in an associated poster. It also discusses new trends in kinase drug discovery programs such as new kinase targets, novel mechanisms of action, and diverse indications...
February 14, 2019: ACS Medicinal Chemistry Letters
https://read.qxmd.com/read/30783324/analysis-of-glycemic-status-in-diabetes-na%C3%A3-ve-patients-on-statins-a-hospital-based-cross-sectional-study
#20
Sereen Rose Thomson, Bharti Chogtu, Ranjan Shetty, Tom Devasia
INTRODUCTION: Randomized controlled trials, observational studies, and meta-analysis suggest risk of hyperglycemia in patients on statins, and this association is being viewed with renewed interest globally. The present study has tried to explore the possible diabetogenic effect of statins, the mechanism of this effect, and various comorbidities associated with this causation. MATERIALS AND METHODS: This cross-sectional study was carried out at the Department of Cardiology from October 2015 to March 2017...
November 2018: Indian Journal of Pharmacology
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