Pharmacological Antagonism and the Olfactory Code
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Combined Actions and Interactions of Chemicals in Mixtures the Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals
Combined Actions and Interactions of Chemicals in Mixtures The Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals Miljøministeriet Miljøstyrelsen Combined Actions and Interactions of Chemicals in Mixtures The Toxicological Effects of Exposure to Mixtures of Industrial and Environmental Chemicals FødevareRapport 2003:12 1st Edition, 1st Circulation, August 2003 Copyright: Danish Veterinary and Food Administration 400 copies Printing office: Schultz Price: DKK 320.- incl. VAT ISBN: 87-91399-08-4 ISSN: 1399-0829 (FødevareRapport) Id-number: 2003012 Publications costing money can be bought at book shops or: Danish State Information Centre Phone +45 7010 1881 www.danmark.dk/netboghandel The Danish Veterinary and Food Administration Mørkhøj Bygade 19, DK-2860 Søborg Tel. + 45 33 95 60 00, fax + 45 33 95 60 01 Web site: www.fdir.dk The Danish Veterinary and Food Administration is part of the Danish Ministry of Agriculture, Food and Fisheries. The Danish Veterinary and Food Administration is responsible for the administration, research and control within food and veterinary areas “from farm to fork”, as well as practical matters relating to animal protection (otherwise under the Ministry of Justice). Making of regulations, co-ordination, research and development, take place in the Administrations center in Moerkhoej. The 11 Regional Authorities handle the practical inspection of food and veterinary matters, including import/export etc. The central administration of The Danish Veterinary and Food Administration -
Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-Erbβ
molecules Article Molecular Dynamics of Cobalt Protoporphyrin Antagonism of the Cancer Suppressor REV-ERBβ Taufik Muhammad Fakih 1,2 , Fransiska Kurniawan 1, Muhammad Yusuf 3 , Mudasir Mudasir 4 and Daryono Hadi Tjahjono 1,* 1 School of Pharmacy, Bandung Institute of Technology, Jalan Ganesha 10, Bandung 40135, Indonesia; taufi[email protected] (T.M.F.); [email protected] (F.K.) 2 Department of Pharmacy, Faculty of Mathematics and Natural Sciences, Universitas Islam Bandung, Jalan Rangga Gading 8, Bandung 40116, Indonesia 3 Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Padjadjaran, Jalan Raya Bandung Sumedang Km 21, Sumedang 45363, Indonesia; [email protected] 4 Department of Chemistry, Faculty of Mathematics and Natural Sciences, Universitas Gadjah Mada, Sekip Utara BLS 21, Yogyakarta 55281, Indonesia; [email protected] * Correspondence: [email protected]; Tel.: +62-81-222-400120 Abstract: Nuclear receptor REV-ERBβ is an overexpressed oncoprotein that has been used as a target for cancer treatment. The metal-complex nature of its ligand, iron protoporphyrin IX (Heme), enables the REV-ERBβ to be used for multiple therapeutic modalities as a photonuclease, a photosensitizer, or a fluorescence imaging agent. The replacement of iron with cobalt as the metal center of proto- porphyrin IX changes the ligand from an agonist to an antagonist of REV-ERBβ. The mechanism behind that phenomenon is still unclear, despite the availability of crystal structures of REV-ERBβ in complex with Heme and cobalt protoporphyrin IX (CoPP). This study used molecular dynamic Citation: Fakih, T.M.; Kurniawan, F.; simulations to compare the effects of REV-ERBβ binding to Heme and CoPP, respectively. -
Phenotypic Spandrel: Absolute Discrimination and Ligand Antagonism
Phenotypic spandrel: absolute discrimination and ligand antagonism Paul Fran¸cois Mathieu Hemery Kyle A. Johnson Laura N. Saunders Physics Department, McGill University, Montreal, Quebec, Canada H3A 2T8 Abstract. We consider the general problem of sensitive and specific discrimination between biochemical species. An important instance is immune discrimination between self and not-self, where it is also observed experimentally that ligands just below discrimination threshold negatively impact response, a phenomenon called antagonism. We characterize mathematically the generic properties of such discrimination, first relating it to biochemical adaptation. Then, based on basic biochemical rules, we establish that, surprisingly, antagonism is a generic consequence of any strictly specific discrimination made independently from ligand concentration. Thus antagonism constitutes a \phenotypic spandrel": a phenotype existing as a necessary by-product of another phenotype. We exhibit a simple analytic model of discrimination displaying antagonism, where antagonism strength is linear in distance from detection threshold. This contrasts with traditional proofreading based models where antagonism vanishes far from threshold and thus displays an inverted hierarchy of antagonism compared to simpler models. The phenotypic spandrel studied here is expected to structure many decision pathways such as immune detection mediated by TCRs and FCRIs, as well arXiv:1511.03965v3 [q-bio.MN] 7 Oct 2016 as endocrine signalling/disruption. Phenotypic spandrel: absolute discrimination and ligand antagonism 2 Introduction Recent works in quantitative evolution combined to mathematical modelling have shown that evolution of biological networks is constrained by selected phenotypes in strong unexpected ways. Trade-offs between different functionalities increasingly appear as major forces shaping evolution of complex phenotypes moving on evolutionary Pareto fronts [1, 2]. -
CH223191 Is a Ligand-Selective Antagonist of the Ah (Dioxin) Receptor
TOXICOLOGICAL SCIENCES 117(2), 393–403 (2010) doi:10.1093/toxsci/kfq217 Advance Access publication July 15, 2010 CH223191 Is a Ligand-Selective Antagonist of the Ah (Dioxin) Receptor Bin Zhao,*,† Danica E. DeGroot,* Ai Hayashi,* Guochun He,* and Michael S. Denison*,1 *Department of Environmental Toxicology, University of California, Davis, California 95616; and †State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China 1To whom correspondence should be addressed at Department of Environmental Toxicology, Meyer Hall, One Shields Avenue, University of California, Davis, CA 95616-8588. Fax: (530) 752-3394. E-mail: [email protected]. Downloaded from Received April 22, 2010; accepted July 8, 2010 beta-naphthoflavone (BNF) (Denison et al., 1998; Poland and The aryl hydrocarbon (dioxin) receptor (AhR) is a ligand- Knutson, 1982; Safe, 1990). However, a relatively large number http://toxsci.oxfordjournals.org/ dependent transcription factor that produces a wide range of of natural, endogenous, and synthetic AhR agonists have also biological and toxic effects in many species and tissues. Whereas been identified in recent years whose structures and physico- the best-characterized high-affinity ligands include structurally related halogenated aromatic hydrocarbons (HAHs) and poly- chemical characteristics are dramatically different from the cyclic aromatic hydrocarbons (PAHs), the AhR is promiscuous prototypical HAH and PAH AhR ligands (Denison and Heath- and can also be activated by structurally diverse exogenous and Pagliuso, 1998; Denison and Nagy, 2003; Denison et al., 1998; endogenous chemicals. However, little is known about how these Nguyen and Bradfield, 2008), which suggests that the AhR has diverse ligands actually bind to and activate the AhR. -
Allosteric Antagonism of the A2A Adenosine Receptor by a Series of Bitopic Ligands
cells Article Allosteric Antagonism of the A2A Adenosine Receptor by a Series of Bitopic Ligands Zhan-Guo Gao *, Kiran S. Toti , Ryan Campbell, R. Rama Suresh , Huijun Yang and Kenneth A. Jacobson * Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA; [email protected] (K.S.T.); [email protected] (R.C.); [email protected] (R.R.S.); [email protected] (H.Y.) * Correspondence: [email protected] (Z.-G.G.); [email protected] (K.A.J.) Received: 1 April 2020; Accepted: 10 May 2020; Published: 12 May 2020 Abstract: Allosteric antagonism by bitopic ligands, as reported for many receptors, is a distinct modulatory mechanism. Although several bitopic A2A adenosine receptor (A2AAR) ligand classes were reported as pharmacological tools, their receptor binding and functional antagonism patterns, i.e., allosteric or competitive, were not well characterized. Therefore, here we systematically characterized A2AAR binding and functional antagonism of two distinct antagonist chemical classes. i.e., fluorescent conjugates of xanthine amine congener (XAC) and SCH442416. Bitopic ligands were potent, weak, competitive or allosteric, based on the combination of pharmacophore, linker and fluorophore. Among antagonists tested, XAC, XAC245, XAC488, SCH442416, MRS7352 showed Ki binding values consistent with KB values from functional antagonism. Interestingly, MRS7396, XAC-X-BY630 (XAC630) and 5-(N,N-hexamethylene)amiloride (HMA) were 9–100 times weaker in displacing fluorescent MRS7416 binding than radioligand binding. XAC245, XAC630, MRS7396, MRS7416 and MRS7322 behaved as allosteric A2AAR antagonists, whereas XAC488 and MRS7395 antagonized competitively. Schild analysis showed antagonism slopes of 0.42 and 0.47 for MRS7396 and XAC630, respectively. -
Structure-Based Discovery of Selective Positive Allosteric Modulators Of
Structure-based discovery of selective positive PNAS PLUS allosteric modulators of antagonists for the M2 muscarinic acetylcholine receptor Magdalena Korczynskaa,1, Mary J. Clarkb,1, Celine Valantc,1, Jun Xud, Ee Von Mooc, Sabine Alboldc, Dahlia R. Weissa, Hayarpi Torosyana, Weijiao Huange, Andrew C. Krusef, Brent R. Lydab, Lauren T. Mayc, Jo-Anne Baltosc, Patrick M. Sextonc, Brian K. Kobilkad,e, Arthur Christopoulosc,2, Brian K. Shoicheta,2, and Roger K. Sunaharab,2 aDepartment of Pharmaceutical Chemistry, University of California, San Francisco, CA 94158; bDepartment of Pharmacology, University of California San Diego School of Medicine, La Jolla, CA 92093; cDrug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC 3052, Australia; dBeijing Advanced Innovation Center for Structural Biology, School of Medicine, Tsinghua University, 100084 Beijing, China; eDepartment of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA 94305; and fDepartment of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115 Edited by Robert J. Lefkowitz, Howard Hughes Medical Institute and Duke University Medical Center, Durham, NC, and approved January 5, 2018 (receivedfor review October 14, 2017) Subtype-selective antagonists for muscarinic acetylcholine receptors that treat incontinence mediated via the M3 mAChR often lead to (mAChRs) have long been elusive, owing to the highly conserved dry mouth due to effects at glandular M1 and M3 mAChRs, increase orthosteric binding site. However, allosteric sites of these receptors heart rate via the M2 mAChR, or increase drowsiness (6, 8, 9). Such are less conserved, motivating the search for allosteric ligands that intrafamily off-target effects for the mAChRs have reduced the modulate agonists or antagonists to confer subtype selectivity. -
Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery
molecules Review Molecular Modeling of Histamine Receptors—Recent Advances in Drug Discovery Pakhuri Mehta, Przemysław Miszta and Sławomir Filipek * Biological and Chemical Research Centre, Faculty of Chemistry, University of Warsaw, 02-093 Warsaw, Poland; [email protected] or [email protected] (P.M.); [email protected] (P.M.) * Correspondence: sfi[email protected] Abstract: The recent developments of fast reliable docking, virtual screening and other algorithms gave rise to discovery of many novel ligands of histamine receptors that could be used for treatment of allergic inflammatory disorders, central nervous system pathologies, pain, cancer and obesity. Furthermore, the pharmacological profiles of ligands clearly indicate that these receptors may be considered as targets not only for selective but also for multi-target drugs that could be used for treatment of complex disorders such as Alzheimer’s disease. Therefore, analysis of protein-ligand recognition in the binding site of histamine receptors and also other molecular targets has become a valuable tool in drug design toolkit. This review covers the period 2014–2020 in the field of theoretical investigations of histamine receptors mostly based on molecular modeling as well as the experimental characterization of novel ligands of these receptors. Keywords: histamine receptors; G protein-coupled receptors; computational studies; molecular docking; virtual screening; drug discovery and design Citation: Mehta, P.; Miszta, P.; Filipek, S. Molecular Modeling of 1. Introduction Histamine Receptors—Recent The most recent scientific technologies have crucial applications for drug discovery Advances in Drug Discovery. and design [1–4]. In silico approaches such as virtual screening and molecular docking have Molecules 2021, 26, 1778. -
Combined Toxic Effects of Chemicals in Mixtures Are Handled at Present Within the Areas Covered by the Scientific Panels 2, 4, 5, 7 and 8 in VKM
Combined toxic effects of multiple chemical exposures Vitenskapskomiteen for mattrygghet 1:2008 1:2008 mattrygghet for Vitenskapskomiteen exposures multiple chemical of effects toxic Combined Vitenskapskomiteen for mattrygghet VKM Report 2008: 16 Norwegian Scientific Committee for Food Safety Combined toxic effects of multiple chemical exposures Published by Vitenskapskomiteen for mattrygghet/ Norwegian Scientific Committee for Food Safety 2008. Postboks 4404 Nydalen 0403 Oslo Combined toxic effects of multiple chemical exposures Tel. + 47 21 62 28 00 www.vkm.no ISBN 978-82-8082-232-1 (Printed edition) ISBN 978-82-8082-233-8 (Electronic edition) Combined toxic effects of multiple chemical exposures Published by Vitenskapskomiteen for mattrygghet/ Norwegian Scientific Committee for Food Safety 2008. Postboks 4404 Nydalen 0403 Oslo Tel. + 47 21 62 28 00 www.vkm.no ISBN 978-82-8082-232-1 (Printed edition) ISBN 978-82-8082-233-8 (Electronic edition) VKM Report 2008: 16 Opinion of the Scientific Steering Committee of the Norwegian Scientific Committee for Food Safety Adopted 7 April 2008 Combined toxic effects of multiple chemical exposures 06/404-6 final Combined toxic effects of multiple chemical exposures Jan Alexander Ragna Bogen Hetland Rose Vikse Erik Dybing Gunnar Sundstøl Eriksen Wenche Farstad Bjørn Munro Jenssen Jan Erik Paulsen Janneche Utne Skåre Inger-Lise Steffensen Steinar Øvrebø 2 Combined toxic effects of multiple chemical exposures 06/404-6 final CONTRIBUTORS Persons working for VKM, either as appointed members of the Committee or as ad hoc experts, do this by virtue of their scientific expertise, not as representatives for their employers. The Civil Services Act instructions on legal competence apply for all work prepared by VKM.