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structure activity relationship

Aleksandar Antanasijevic, Nicholas J Hafeman, Smanla Tundup, Carolyn Kingsley, Rama K Mishra, Lijun Rong, Balaji Manicassamy, Duncan Wardrop, Michael Caffrey
The viral envelope protein hemagglutinin (HA) plays a critical role in influenza entry and thus is an attractive target for novel therapeutics. The small molecule tert-butylhydroquinone (TBHQ) has previously been shown to bind to HA and inhibit HA-mediated entry with low micromolar potency. However, enthusiasm for the use of TBHQ has diminished due to the compound's antioxidant properties. In this work we show that the antioxidant properties of TBHQ are not responsible for the inhibition of HA-mediated entry...
September 9, 2016: ACS Infectious Diseases
Sher Ali, Tao Xu, Xiaolan Xu
Ca(2+) release-activated Ca(2+) (CRAC) channels play an essential role in the immune system. The pore-forming subunit, Orai1, is an important pharmacological target. Here, we summarize the recent discoveries on the structure-function relationship of Orai1, as well as its interaction with the native channel opener STIM1 and chemical modulator 2-aminoethoxydiphenyl borate (2-APB). We first introduce the critical structural elements of Orai1, which include a Ca(2+) accumulating region (CAR), ion selectivity filter, hydrophobic centre, basic region, extended transmembrane orai1 N-terminal (ETON), transmembrane (TM) regions 2 and 3, P245 bend, (263) SHK(265) hinge linker and L273-L276 hydrophobic patch...
October 18, 2016: Journal of Physiology
Jenny L Wiley, Julie A Marusich, Brian F Thomas
Originally developed as research tools for use in structure-activity relationship studies, synthetic cannabinoids contributed to significant scientific advances in the cannabinoid field. Unfortunately, a subset of these compounds was diverted for recreational use beginning in the early 2000s. As these compounds were banned, they were replaced with additional synthetic cannabinoids with increasingly diverse chemical structures. This chapter focuses on integration of recent results with those covered in previous reviews...
October 18, 2016: Current Topics in Behavioral Neurosciences
Chao Yang, Iris L K Wong, Kai Peng, Zhen Liu, Peng Wang, Tingfu Jiang, Tao Jiang, Larry M C Chow, Sheng Biao Wan
In the present study, a total of 25 novel ningalin B analogues were synthesized and evaluated for their P-gp modulating activity in a P-gp overexpressed breast cancer cell line LCC6MDR. Preliminary structure-activity study shows that A ring and its two methoxy groups are important pharmacophores for P-gp inhibiting activity. Among all derivatives, 23 is the most potent P-gp modulator with EC50 of 120-165 nM in reversing paclitaxel, DOX, vinblastine and vincristine resistance. It is relatively safe to use with selective index at least greater than 606 compared to verapamil...
September 22, 2016: European Journal of Medicinal Chemistry
Yves Claude Guillaume, Lydie Lethier, Claire André
TRAIL is a member of the TNF family of cytokines which induces apoptosis of cancer cells via its binding to its cognate receptors, DR5 a high affinity site and DR4 a site of low affinity. Our working group has recently demonstrated that nanovectorization of TRAIL with single wall carbon nanotubes (abbreviated NPT) enhanced TRAIL affinity to the high affinity site DR5 and increased pro apoptotic potential in different human tumor cell lines. In this paper, the DR4 low affinity site was immobilized on a chromatographic support and the effect of temperature on a wide temperature range 1°C-50°C was studied to calculate the thermodynamic parameters of the binding of TRAIL and NPT to DR4 and DR5 receptors...
October 12, 2016: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Yang Liu, Xia Peng, Xiaocong Guan, Dong Lu, Yong Xi, Shiyu Jin, Hui Chen, Limin Zeng, Jing Ai, Meiyu Geng, Youhong Hu
FGF receptors (FGFRs) are tyrosine kinases that are overexpressed in diverse tumors by genetic alterations such as gene amplifications, somatic mutations and translocations. Owing to this characteristic, FGFRs are attractive targets for cancer treatment. It has been demonstrated that most multi-targeted, ATP competitive tyrosine kinase inhibitors are active against FGFRs as well as other kinases. The design of new and more selective inhibitors of FGFRs, which might be reduced off-target and side effects, is a difficult yet significant challenge...
October 4, 2016: European Journal of Medicinal Chemistry
Jone Corrales, Lauren A Kristofco, W Baylor Steele, Gavin N Saari, Jakub Kostal, Edward Spencer Williams, Margaret Mills, Evan P Gallagher, Terrance J Kavanagh, Nancy Simcox, Longzhu Q Shen, Fjodor Melnikov, Julie B Zimmerman, Adelina M Voutchkova-Kostal, Paul T Anastas, Bryan W Brooks
Sustainable molecular design of less hazardous chemicals presents a potentially transformative approach to protect public health and the environment. Relationships between molecular descriptors and toxicity thresholds previously identified the octanol-water distribution coefficient, log D, and the HOMO-LUMO energy gap, ∆E, as two useful properties in the identification of reduced aquatic toxicity. To determine whether these two property-based guidelines are applicable to sublethal oxidative stress (OS) responses, two common aquatic in vivo models, the fathead minnow (Pimephales promelas) and zebrafish (Danio rerio), were employed to examine traditional biochemical biomarkers (lipid peroxidation, DNA damage, total glutathione) and antioxidant gene activation following exposure to eight structurally diverse industrial chemicals (bisphenol A, cumene hydroperoxide, dinoseb, hydroquinone, indene, perfluorooctanoic acid, R-(-)-carvone, tert-butyl hydroperoxide)...
October 17, 2016: Chemical Research in Toxicology
Efeturi Abraham Onoabedje, Akachukwu Ibezim, Sunday Nwankwor Okafor, Ufuoma Shalom Onoabedje, Uchechukwu Chris Okoro
Penicillin binding proteins (PBPs) are normal constituents of bacterial which are absent in mammalian cells. The theoretical binding modes of known oxazin-5-ones toward the protein were used as a guide to synthesis new inhibitors. Structural studies of protein-ligand complexes revealed that conformational discrepancies of the derivatives in the protein's binding site gave rise to the variation in their inhibition constant which ranged from 68.58 μM to 2.04 mM. Biological assay results further confirmed the antibiotic potencies of the studied compounds...
2016: PloS One
Yohei Manabe, Marie Yoshimura, Kazuma Sakamaki, Asuka Inoue, Aya Kakinoki, Satoshi Hokari, Mariko Sakanaka, Junken Aoki, Hiroyuki Miyachi, Kazuyuki Furuta, Satoshi Tanaka
Accumulating evidence suggests that activated mast cells are involved in contact hypersensitivity, although the precise mechanisms of their activation are still not completely understood. We investigated the potential of common experimental allergens to induce mast cell activation using murine bone marrow-derived cultured mast cells and rat peritoneal mast cells. Among these allergens, 1-chloro-2,4-dinitrobenzene and 1-fluoro-2,4-dinirobenzene (DNFB) were found to induce degranulation of rat peritoneal mast cells...
October 17, 2016: European Journal of Immunology
Alex Maolanon, Helle Kristensen, Luke Leman, Reza Ghadiri, Christian Adam Olsen
Inhibition of histone deacetylase (HDAC) enzymes has emerged as a target for development of cancer chemotherapy. Four compounds have gained approval for clinical use by the Food and Drug Administration (FDA) in the US, and several are currently in clinical trials. However, none of these compounds possesses particularly good isozyme-selectivity, which would be a highly desirable feature in a tool compound. Whether selective inhibition of individual HDAC isozymes will provide improved drug candidates remains to be seen...
October 17, 2016: Chembiochem: a European Journal of Chemical Biology
Carolyn N Haarmeyer, Matthew D Smith, Shishir Chundawat, Deanne Sammond, Timothy A Whitehead
Biological-mediated conversion of pretreated lignocellulosic biomass to biofuels and biochemicals is a promising avenue towards energy sustainability. However, a critical impediment to the commercialization of cellulosic biofuel production is the high cost of cellulase enzymes needed to deconstruct biomass into fermentable sugars. One major factor driving cost is cellulase adsorption and inactivation in the presence of lignin, yet we currently have a poor understanding of the protein structure-function relationships driving this adsorption...
October 17, 2016: Biotechnology and Bioengineering
Ho Shin Kim, Mannkyu Hong, Jihyae Ann, Suyoung Yoon, Cong-Truong Nguyen, Su-Chan Lee, Ho-Young Lee, Young-Ger Suh, Ji Hae Seo, Hoon Choi, Jun Yong Kim, Kyu-Won Kim, Joohwan Kim, Young-Myeong Kim, So-Jung Park, Hyun-Ju Park, Jeewoo Lee
Based on the lead compound L-80 (compound 2), a potent heat shock protein 90 (HSP90) inhibitor, a series of C-ring truncated deguelin analogs were designed, synthesized and evaluated for Hypoxia Inducible Factor-1α (HIF-1α) inhibition as a primary screening method. Their structure-activity relationship was investigated in a systematic manner by varying the A/B ring, linker and D/E ring, respectively. Among the synthesized inhibitors, compound 5 exhibited potent HIF-1α inhibition in a dose-dependent manner and significant antitumor activity in human non-small cell lung carcinoma (H1299), with better activities than L-80...
September 30, 2016: Bioorganic & Medicinal Chemistry
Sudipta Saha, Vinit Raj, Amit Rai
The chemistry of heterocyclic containing, 1,3,4-thiadiazole has been an interesting field of study from ancient years. Subsequently, 1,3,4-thiadiazole nucleus constitutes a significant class of compounds for new drug development. Recently, various 1,3,4-thiadiazole derivatives have been synthesized and evaluated their biological activities including antimicrobial, antituberculosis, antioxidant, anti-inflammatory, anticonvulsants, antidepressant and anxiolytic, antihypertensive, anticancer and antifungal activity...
October 13, 2016: Anti-cancer Agents in Medicinal Chemistry
Michela De Bellis, Roberta Carbonara, Julien Roussel, Alessandro Farinato, Ada Massari, Sabata Pierno, Marilena Muraglia, Filomena Corbo, Carlo Franchini, Maria Rosaria Carratù, Annamaria De Luca, Diana Conte Camerino, Jean-François Desaphy
Although the sodium channel blocker, mexiletine, is the first choice drug in myotonia, some myotonic patients remain unsatisfied due to contraindications, lack of tolerability, or incomplete response. More therapeutic options are thus needed for myotonic patients, which require clinical trials based on solid preclinical data. In previous structure-activity relationship studies, we identified two newly-synthesized derivatives of tocainide, To040 and To042, with greatly enhanced potency and use-dependent behavior in inhibiting sodium currents in frog skeletal muscle fibers...
October 12, 2016: Neuropharmacology
Jovana Trifunović, Vladan Borčić, Momir Mikov
Some biological properties of bile acids and their oxo derivatives have not been sufficiently investigated, although the interest for bile acids as signaling molecules is rising. The aim of this work was to evaluate physico-chemical parametar b (slope) that represents lipophilicity of the examined molecules and to investigate interactions of bile acids with carbonic anhydrase I, II, androgen receptor and CYP450s. 13 candidates were investigated using normal phase thin layer chromatography in two solvent systems...
October 14, 2016: Biomedical Chromatography: BMC
Sukhithasri Vijayrajratnam, Anju Choorakottayil Pushkaran, Aathira Balakrishnan, Anilkumar Vasudevan, Raja Gopi Biswas, Chethampadi Gopi Mohan
Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is an intracellular pattern recognition receptor that recognizes bacterial peptidoglycan (PG) containing meso -diaminopimelic acid ( meso DAP) and activates the innate immune system. Interestingly, few pathogenic and commensal bacteria modify their PG stem peptide by amidation of meso DAP ( meso DAPNH2). In this study, NOD1 stimulation assays were performed using bacterial PG containing meso DAP (PGDAP) and meso DAPNH2 (PGDAPNH2) to understand the differences in their biomolecular recognition mechanism...
October 14, 2016: Biochemical Journal
Anna K Taylor, Maria Loades, Amberly Lc Brigden, Simon M Collin, Esther Crawley
BACKGROUND: Paediatric chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) has a prevalence of 0.4-2.4% and is defined as 'generalised disabling fatigue persisting after routine tests and investigations have failed to identify an obvious underlying cause'. One-third of young people with CFS/ME have probable depression. Little is known about why depression develops, the relationship between depression and CFS/ME, or what treatment might be helpful. METHODS: We conducted nine semi-structured interviews with young people with CFS/ME (aged 13-17 years, 8/9 female) and probable depression, covering perceived causes of depression, the relationship between CFS/ME and depression, and treatment strategies...
October 14, 2016: Clinical Child Psychology and Psychiatry
Dongwei Kang, Heng Zhang, Zhongxia Zhou, Boshi Huang, Lieve Naesens, Peng Zhan, Xinyong Liu
A series of 1,2,3-triazolyl 3-hydroxy-quinazoline-2,4(1H,3H)-diones was constructed utilizing Cu(I)-catalyzed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) method. The biological significance of the novel synthesized quinazolines was highlighted by evaluating them in vitro for antiviral activity, wherein several compounds exhibited excellent activity specifically against vaccinia and adenovirus. Especially, 24b11 displayed the most potent inhibitory activity against vaccinia with an EC50 value of 1.7μM, which was 15 fold than that of the reference drug Cidofovir (EC50=25μM)...
September 29, 2016: Bioorganic & Medicinal Chemistry Letters
Björn Borgström, Xiaoli Huang, Cecilia Hegardt, Stina Oredsson, Daniel Strand
The ionophore salinomycin has attracted attention for its exceptional ability to selectively reduce the proportion of cells with stem-like properties in cancer cell populations of varying origin. Targeting the tumorigenicity of such cells is of interest as they are implicated in recurrence, metastasis, and drug resistance. Structural derivatives of salinomycin are thus sought after, both as tools for probing the molecular mechanism(s) underlying the observed phenotype effects, and for improving selectivity and activity against cancer stem cells...
October 14, 2016: Chemistry: a European Journal
Chun-Hui Zhang, Kai Chen, Yan Jiao, Lin-Li Li, Ya-Ping Li, Rong-Jie Zhang, Ming-Wu Zheng, Lei Zhong, Shen-Zhen Huang, Chun-Li Song, Wan-Ting Lin, Jiao Yang, Rong Xiang, Bing Peng, Jun-Hong Han, Guang-Wen Lu, Yu-Quan Wei, Sheng-Yong Yang
Herein we report the sophisticated process of structural optimization towards a previously disclosed Src inhibitor, compound 1, which showed high potency in the treatment of triple negative breast cancer (TNBC) both in vitro and in vivo, but had considerable toxicity. A series of 3-(phenylethynyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine derivatives were synthesized. In vitro cell-based phenotypic screening together with in vivo assays, and structure-activity relationship (SAR) studies finally led to the discovery of N-(3-((4-amino-1-(trans-4-hydroxycyclohexyl)-1H-pyrazolo[3,4-d]pyrimidin-3-yl)ethynyl)-4-methylphenyl)-4-methyl-3-(trifluoromethyl)benzamide (13an)...
October 14, 2016: Journal of Medicinal Chemistry
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