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Receptors And Lead Compound

Patrick Caron, Véronique Turcotte, Eric Lévesque, Chantal Guillemette
Abiraterone acetate (AA) is a prodrug of abiraterone, a selective and potent steroidal cytochrome P450 17alpha- hydroxylase-17,20-lyase (CYP17A1) blocking androgen synthesis in the treatment of advanced prostate cancer. Abiraterone (Abi) is metabolized to D(4)-abiraterone (D4A) directly blocking CYP17A1 and other steroidogenic enzymes and antagonizing the androgen receptor (AR). D4A is converted by 5α-reductase to 3-keto-5α-abiraterone (5α-Abi), an AR agonist. Our recent work suggests phase II biotransformation of Abi, D4A and 5α-Abi conjugated to glucuronic acid in vitro leading to four glucuronides (G)...
December 4, 2018: Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences
Kavitha Rani P R, Y Sheena Mary, Annette Fernandez, Anu Priya S, Y Shyma Mary, Renjith Thomas
A derivative of naphthaquinone, 2-((1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)amino)naphthalene-1,4-dione (DPDHN) was synthesized from lawsone by ultrasound accelerated technique. The compound was characterized by elemental analysis, IR, UV-vis, NMR and mass spectral studies. Single crystal X-ray diffraction studies revealed that the compound crystallized in monoclinic space group P21 /c. Density functional calculations of DPDHN was performed using DFT (B3LYP) method with 6-311G (5D, 7F) basis set, geometrical optimization best fit to single crystal XRD values...
November 30, 2018: Computational Biology and Chemistry
Dorota Łażewska, Rafał Kurczab, Małgorzata Więcek, Grzegorz Satała, Katarzyna Kieć-Kononowicz, Jadwiga Handzlik
A series of 2-amino-4-(4-methylpiperazin-1-yl)-1,3,5-triazines was designed based on previously published 2-amino-4-benzyl-(4-methylpiperazin-1-yl)-1,3,5-triazines in order to evaluate the role of a linker between the triazine moiety and an aromatic substituent for the human serotonin 5-HT6 receptor affinity. As new linkers two carbon atoms (ethyl or ethenyl) or an oxyalkyl chain (methoxy, 2-ethoxy, 2-propoxy) were introduced. Affinities of the compounds for the 5-HT6 R as the main target, and for the 5-HT1A R, 5-HT7 R and D2 R as competitive ones, were determined in the radioligand binding assays...
November 26, 2018: Bioorganic Chemistry
Silvain Pinaud, Anaïs Portet, Jean-François Allienne, Lucid Belmudes, Cécile Saint-Beat, Nathalie Arancibia, Richard Galinier, Louis Du Pasquier, David Duval, Benjamin Gourbal
Invertebrate immune response may be primed by a current infection in a sustained manner, leading to the failure of a secondary infection with the same pathogen. The present study focuses on the Schistosomiasis vector snail Biomphalaria glabrata, in which a specific genotype-dependent immunological memory was demonstrated as a shift from a cellular to a humoral immune response. Herein, we investigate the complex molecular bases associated with this genotype-dependant immunological memory response. We demonstrate that Biomphalaria regulates a polymorphic set of immune recognition molecules and immune effector repertoires to respond to different strains of Schistosoma parasites...
December 4, 2018: Developmental and Comparative Immunology
Pio Conti, Cristian D'Ovidio, Chiara Conti, Carla Enrica Gallenga, Dorina Lauritano, Alessandro Caraffa, Spiros K Kritas, Gianpaolo Ronconi
Migraine is a common painful neurovascular disorder usually associated with several symptoms, such as photophobia, phonophobia, nausea, vomiting and inflammation, and involves immune cells. Mast cells (MCs) are immune cells derived from hematopoietic pluripotent stem cells which migrate and mature close to epithelial, blood vessels, and nerves. In almost all vascularized tissues there are MCs that produce, contain and release biologically active products including cytokines, arachidonic acid compounds, and proteases...
December 6, 2018: European Journal of Pharmacology
Jorge De La Chapa, Matthew Valdez, Franscisco Ruiz, Keith Gonzales, Wes Mitchell, Stanton F McHardy, Matthew Hart, Srikanth R Polusani, Cara B Gonzales
We previously demonstrated that capsazepine (CPZ), a synthetic transient receptor potential Vanilloid subtype 1 (TRPV1) antagonist, has significant anti-cancer effects in vivo. The purpose of this study was to develop more potent analogs based upon CPZ pharmacophore and structure-activity relationships (SAR) across analogs. We generated 30 novel compounds and screened for their anti-proliferative effects in cultured HeLa cervical cancer cells. Cell viability assays identified multiple compounds with IC50s  < 15 μM and one compound, 29 with an IC50  < 5 μM; six fold more potent than CPZ...
November 29, 2018: Bioorganic & Medicinal Chemistry
Yueying Li, Yuntao Liu, Xia Yan, Qing Liu, Yong-Hua Zhao, Da-Wei Wang
Cardio/cerebral-vascular diseases seriously threaten human health and are the leading cause of death. As such, there is great interest in identifying a potential mechanism that controls the development process of cardio/cerebral vascular diseases. Present studies demonstrate that inflammasomes play an important role in the process of ischemic cardio/cerebral vascular diseases (ICCVDs). Among the pathological process of ICCVDs, inflammasomes activated the sterile inflammatory response that accelerated the development of diseases and aggravated the acute lesion of tissue...
December 10, 2018: American Journal of Chinese Medicine
Maria Yousuf, Nimra Naveed Shaikh, Zaheer Ul-Haq, M Iqbal Choudhary
Identification of hotspot drug-receptor interactions through in-silico prediction methods (Pharmacophore mapping, virtual screening, 3DQSAR, etc), is considered as a key approach in drug designing and development process. In the current design study, advanced in-silico based computational techniques were used for the identification of lead-like molecules against the targeted receptor β-glucuronidase. The binding pattern of a potent inhibitor in the ligand-receptor X-ray co-crystallize complex was used to identify and extract the structure-base Pharmacophore features...
2018: PloS One
Lina T Al Kury, Mohamed Mahgoub, Frank Christopher Howarth, Murat Oz
Chemotherapy-induced nausea and vomiting (CINV) remain the most common and devastating side-effects associated with cancer chemotherapy. In recent decades, several lines of research emphasize the importance of 5-hydroxytryptamine3 (5-HT3; serotonin) receptors in the pathogenesis and treatment of CINV. 5-HT₃ receptors are members of ligand-gated ion channels that mediate the rapid and transient membrane-depolarizing effect of 5-HT in the central and peripheral nervous system. These receptors play important roles in nausea and vomiting, as well as regulation of peristalsis and pain transmission...
December 3, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Xin Xue, Gang Bao, Hai-Qing Zhang, Ning-Yi Zhao, Yuan Sun, Yue Zhang, Xiao-Long Wang
: The judicious application of ligand or binding efficiency (LE) metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Here we report for the first time the use of LE based metric, fit quality (FQ), in virtual screening (VS) of MDM2/p53 protein-protein interaction inhibitors (PPIIs). Firstly, a Receptor-Ligand pharmacophore model was constructed on multiple MDM2/ligand complex structures to screen the library...
December 1, 2018: Molecules: a Journal of Synthetic Chemistry and Natural Product Chemistry
Trond Vidar Hansen, Jørn Eivind Tungen, Lisa Gerstman, Roberta De Matteis, Romain Alexandre Colas, Anders Vik, Nan Chiang, Charles Nicholas Serhan, Markus Kalesse, Jesmond Dalli
New drugs that can resolve inflammation without immunosuppressive effects are at the medicinal chemistry frontier. Pro-resolving endogenously formed small molecules, i.e. the resolvins, are excellent candidates displaying such bioactions. The first total synthesis of the specialized pro-resolving mediator RvD1n-3 DPA has been achieved using the underutilized sp3-sp3 Negishi cross coupling reaction and an alkyne hydrosilylation-protodesilylation protocol. Biological evaluations revealed that this novel mediator displays low nanomolar pro-resolving properties and potently activates the human DRV1/GPR32 receptor...
December 4, 2018: Chemistry: a European Journal
Balraj Singh Gill, Navgeet, Sanjeev Kumar
Neuroblastoma is a childhood tumor arising from developing a sympathetic nervous system and causes around 10% of pediatric tumors. Despite advancement in the use of sophisticated techniques in molecular biology, neuroblastoma patient's survivability rate is very less. Notch pathway is significant in upholding cell maintenance and developmental process of organs. Notch-1 proteins are a ligand-activated transmembrane receptor which decides the fate of the cell. Notch signaling leads to transcription of genes which indulged in numerous diseases including tumor progression...
December 3, 2018: Molecular and Cellular Biochemistry
Elin Pauwels, Frederik Cleeren, Guy Bormans, Christophe M Deroose
Somatostatin receptors (SSTRs) are variably expressed by a variety of malignancies. Using radiolabeled somatostatin analogs (SSAs), the presence of SSTRs on tumor cells may be exploited for molecular imaging and for peptide receptor radionuclide therapy. 111 In-DTPA-octreotide has long been the standard in SSTR scintigraphy. A major leap forward was the introduction of gallium-68 labeled SSAs for positron emission tomography (PET) offering improved sensitivity. Tracers currently in clinical use are 68 Ga-DOTA-Tyr3 -octreotide (68 Ga-DOTATOC), 68 Ga-DOTA-Tyr3 -octreotate (68 Ga-DOTATATE) and 68 Ga-DOTA-1-NaI3 -octreotide (68 Ga-DOTANOC), collectively referred to as 68 Ga-DOTA-peptides...
2018: American Journal of Nuclear Medicine and Molecular Imaging
Zhenjian Lin, Sujal Phadke, Zhenyu Lu, Sinem Beyhan, May H Abdel Aziz, Chris Reilly, Eric W Schmidt
We report an unusual 3-substituted pyridine polyketide, onydecalin A (1), which was obtained along with 2 as a major constituent from the fungus Aioliomyces pyridodomos (order: Onygenales) following a two-month fermentation. Feeding studies demonstrated that the pyridine subunit originates via an unprecedented biosynthetic process in comparison to other polyketide-linked pyridines or derivatives such as pyridones. The slow growth of the fungus led us to perform a one-year fermentation, leading to production of compounds 2-4 as the major constituents...
December 3, 2018: Journal of Natural Products
Yuxin Wang, Weicang Wang, Haixia Yang, Derek Shao, Xinfeng Zhao, Guodong Zhang
Human and animal studies have shown that the colonic concentrations of lipid peroxidation products, such as 4-hydroxynonenal (4-HNE), are elevated in inflammatory bowel disease (IBD). However, the actions and mechanisms of these compounds on the development of IBD are unknown. Here, we show that a systemic treatment of low-dose 4-HNE exacerbates dextran sulfate sodium (DSS)-induced IBD in C57BL/6 mice, suggests its pro-IBD actions in vivo. Treatment with 4-HNE suppressed colonic expressions of tight-junction protein occludin, impaired intestinal barrier function, enhanced translocation of lipopolysaccharide (LPS), and bacterial products from the gut into systemic circulation, lead to an increased activation of Toll-like receptor 4 (TLR4) signaling in vivo...
November 29, 2018: Free Radical Biology & Medicine
Janis C Weeks, Kristin J Robinson, Shawn R Lockery, William M Roberts
Many anthelmintic drugs used to treat parasitic nematode infections target proteins that regulate electrical activity of neurons and muscles: ion channels (ICs) and neurotransmitter receptors (NTRs). Perturbation of IC/NTR function disrupts worm behavior and can lead to paralysis, starvation, immune attack and expulsion. Limitations of current anthelmintics include a limited spectrum of activity across species and the threat of drug resistance, highlighting the need for new drugs for human and veterinary medicine...
October 30, 2018: International Journal for Parasitology, Drugs and Drug Resistance
Teresa Żołek, Orsolya Dömötör, Kinga Ostrowska, Éva A Enyedy, Dorota Maciejewska
The delivery of drugs to the brain is complicated by the multiple factors including low blood-brain barrier (BBB) passive permeability, active BBB efflux systems, and plasma protein binding. Thus, a detailed understanding of the transport of the new potent substances through the membranes is vitally important and their physico-chemical characteristics should be analyzed at first. This work presents an evaluation of drug likeness of eight 7-O-arylpiperazinylcoumarin derivatives with high affinity towards serotoninergic receptors 5-HT1A and 5-HT2A with particular analysis of the requirements for the CNS chemotherapeutics...
November 22, 2018: Bioorganic Chemistry
Zhong-Rui Li, Feng-Zhi Suo, Bo Hu, Yan-Jia Guo, Dong-Jun Fu, Bin Yu, Yi-Chao Zheng, Hong-Min Liu
Osimertinib (AZD9291) is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) that has been approved for the treatment of EGFR-mutated non-small cell lung cancer (NSCLC). In this study, osimertinib was characterized as a LSD1 inhibitor for the first time with an IC50 of 3.98 ± 0.3 μM and showed LSD1 inhibitory effect at cellular level. These findings provide new molecular skeleton for dual inhibitor for LSD1 and EGFR. Osimertinib could serve as a lead compound for further development for anti-NSCLC drug discovery with dual targeting...
November 16, 2018: Bioorganic Chemistry
Joseph E Pero, Jay Matthews, David J Behm, Edward Brnardic, Carl A Brooks, Brian W Budzik, Melissa Costell, Carla Donatelli, Stephen Eisennagel, Karl F Erhard, Michael Fischer, Dennis A Holt, Larry Jolivette, Huijie Li, Peng Li, John McAtee, Brent W McCleland, Israil Pendrak, Lorraine Posobiec, Katrina Rivera, Ralph A Rivero, Theresa J Roethke, Matthew Sender, Arthur Shu, Lamont Terrell, Kalindi Vaidya, Xiaoping Xu, Brian G Lawhorn
Pulmonary edema is a common ailment of heart failure patients and has remained an unmet medical need due to dose-limiting side effects associated with current treatments. Preclinical studies in rodents have suggested that inhibition of TRPV4 cation channels may offer an alternative - and potentially superior - therapy. Efforts directed toward small molecule antagonists of the TRPV4 receptor have led to the discovery of a novel sulfone pyrrolidine sulfonamide chemotype exemplified by lead compound 6. Design elements toward the optimization of TRPV4 activity, selectivity and pharmacokinetic properties are described...
November 30, 2018: Journal of Medicinal Chemistry
Khushboo Sharma, Khushboo Patidar, Meer Asif Ali, Pravin Patil, Elizabeth Anne Hood, Anuraj Nayarisseri
Renal Cell Carcinoma is a common type of renal cancer-causing deaths worldwide is characterized by sustained angiogenesis. VEGF and its receptors play a major role in physiologic and pathologic angiogenesis, which is marked in tumour progression and metastasis development. Induction of VEGF genes occur due to hypoxic condition induced by tumour growth after a critical size in cancerous cell. Signal transduction networks originated by VEGFA/VEGFR2, (a notable ligand-receptor complex in the VEGF system) leads to major angiogenesis events ranging from endothelial cell proliferation, to new vessel formation, Furthermore, differential expression of VEGF-VEGFR mRNA also found in different types of RCC...
November 30, 2018: Current Topics in Medicinal Chemistry
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