Small Molecule Modulators of Amine Oxidation, Nuclear Receptor Signaling and Glucuronidation PDF
Preview Small Molecule Modulators of Amine Oxidation, Nuclear Receptor Signaling and Glucuronidation
JYVÄSKYLÄ STUDIES IN BIOLOGICAL AND ENVIRONMENTAL SCIENCE 345 Sanna Rauhamäki Small Molecule Modulators of Amine Oxidation, Nuclear Receptor Signaling and Glucuronidation 3-Phenylcoumarin as a Scaffold of Interest JYVÄSKYLÄ STUDIES IN BIOLOGICAL AND ENVIRONMENTAL SCIENCE 345 Sanna Rauhamäki Small Molecule Modulators of Amine Oxidation, Nuclear Receptor Signaling and Glucuronidation 3-Phenylcoumarin as a Scaffold of Interest Esitetään Jyväskylän yliopiston matemaattis-luonnontieteellisen tiedekunnan suostumuksella julkisesti tarkastettavaksi yliopiston Ambiotica-rakennuksen salissa YAA303 huhtikuun 20. päivänä 2018 kello 12. Academic dissertation to be publicly discussed, by permission of the Faculty of Mathematics and Science of the University of Jyväskylä, in building Ambiotica, hall YAA303, on April 20, 2018 at 12 o’clock noon. UNIVERSITY OF JYVÄSKYLÄ JYVÄSKYLÄ 2018 Small Molecule Modulators of Amine Oxidation, Nuclear Receptor Signaling and Glucuronidation 3-Phenylcoumarin as a Scaffold of Interest JYVÄSKYLÄ STUDIES IN BIOLOGICAL AND ENVIRONMENTAL SCIENCE 345 Sanna Rauhamäki Small Molecule Modulators of Amine Oxidation, Nuclear Receptor Signaling and Glucuronidation 3-Phenylcoumarin as a Scaffold of Interest UNIVERSITY OF JYVÄSKYLÄ JYVÄSKYLÄ 2018 Editors Varpu Marjomäki Department of Biological and Environmental Science, University of Jyväskylä Pekka Olsbo, Ville Korkiakangas Publishing Unit, University Library of Jyväskylä Jyväskylä Studies in Biological and Environmental Science Editorial Board Jari Haimi, Anssi Lensu, Timo Marjomäki, Varpu Marjomäki Department of Biological and Environmental Science, University of Jyväskylä Cover picture by Sanna Rauhamäki. Permanent link to this publication: http://urn.fi/URN:ISBN:978-951-39-7397-1 URN:ISBN:978-951-39-7397-1 ISBN 978-951-39-7397-1 (PDF) ISBN 978-951-39-7396-4 (nid.) ISSN 1456-9701 Copyright © 2018, by University of Jyväskylä Jyväskylä University Printing House, Jyväskylä 2018 “We need to concentrate on more than meets the eye” Twenty Years by Placebo ABSTRACT Rauhamäki, Sanna Small Molecule Modulators of Amine Oxidation, Nuclear Receptor Signaling and Glucuronidation – 3-Phenylcoumarin as a Scaffold of Interest Jyväskylä: University of Jyväskylä, 2018, 91 p. (Jyväskylä Studies in Biological and Environmental Science ISSN 1456-9701; 345) ISBN 978-951-39-7396-4 (nid.) ISBN 978-951-39-7397-1 (PDF) Yhteenveto: Pienmolekyylit amiinien oksidaation, tumareseptorien signaloinnin ja glukuronidaation muovaajina – 3-fenyylikumariini tutkimuksen kohteena Diss. The costs of the drug development process are moderated as computer-aided drug design methods are able to expedite the steps required for lead identification. In fact, computational tools are nowadays virtually indispensable from target identification and validation to preclinical tests due to exponential growth of available information regarding both potential targets and small molecules. One such small molecule with growing number of variations is coumarin. Coumarin scaffold and its various derivatives continue to interest researchers for their vast application potential. Since naturally occurring coumarins are known for example for their antioxidant and anti-inflammatory properties, those molecules are used to guide research endeavors toward similar molecules but with enhanced or newly directed activities. In this doctoral thesis, coumarin derivatives are used to gain novel details regarding monoamine oxidase and nuclear receptor modulation in context relevant for example in neurological conditions and cancer. In order to achieve this, diverse collection of coumarin derivatives is investigated in these targets and corresponding antitargets using both computational and experimental methods. As a result, novel coumarin derivatives with activity in nanomolar range are identified in case of monoamine oxidase B and estrogen receptor (cid:450) and comparable activity is reached for retinoid-acid-receptor-related orphan receptor (cid:452)t with novel core. In addition, the usability of coumarin derivatives as assay development tools is put to test by designing selective ligands for glucuronidation. Consequently, the metabolic fate of the coumarins is investigated as they are allocated to metabolizing target using homology models, computational methods and experimental techniques. Subsequently, two coumarin derivatives selective for human uridine 5'-diphospho-glucuronosyltransferase 1A10 are identified. Keywords: 3-phenylcoumarin, 17(cid:451)-hydroxysteroid dehydrogenase, cancer, computer-aided drug design, estrogen receptor, monoamine oxidase. Sanna Rauhamäki, University of Jyväskylä, Department of Biological and Environmental Science, P.O. Box 35, FI-40014 University of Jyväskylä, Finland Author’s address Sanna Rauhamäki Department of Biological and Environmental Science P.O. Box 35 FI-40014 University of Jyväskylä Finland [email protected] Supervisors Professor Olli Pentikäinen, Ph.D. Department of Biological and Environmental Science P.O. Box 35 FI-40014 University of Jyväskylä Finland Docent Ulla Pentikäinen, Ph.D. Department of Biological and Environmental Science P.O. Box 35 FI-40014 University of Jyväskylä Finland Docent Pekka Postila, Ph.D. Department of Biological and Environmental Science P.O. Box 35 FI-40014 University of Jyväskylä Finland Reviewers Docent Henri Xhaard, Ph.D. Division of Pharmaceutical Chemistry and Technology P.O. Box 56 FI-00014 University of Helsinki Finland Docent Lari Lehtiö, Ph.D. Biocenter Oulu and Faculty of Biochemistry and Molecular Medicine P.O. Box 3000 FI-90014 University of Oulu Finland Opponent Docent Maija Lahtela-Kakkonen, Ph.D. School of Pharmacy P.O. Box 1627 FI-70211 University of Eastern Finland Finland CONTENTS ABSTRACT CONTENTS LIST OF ORIGINAL PUBLICATIONS RESPONSIBILITIES OF SANNA RAUHAMÄKI IN THE ORIGINAL PUBLICATIONS OF THE THESIS ABBREVIATIONS 1 INTRODUCTION ..................................................................................................... 9 2 REVIEW OF LITERATURE ................................................................................... 11 2.1 Monoamine oxidases ...................................................................................... 11 2.1.1 Clinical significance and pharmacology of MAOs ......................... 14 2.2 Nuclear receptors ............................................................................................ 16 2.2.1 Estrogen receptor (cid:450) and the estradiol synthesis pathway ............. 17 2.2.2 Clinical significance of the estradiol synthesis pathways .............. 19 2.2.3 Retinoid-acid-receptor-related orphan receptor (cid:452)t ......................... 20 2.3 Uridine 5'-diphospho-glucuronosyltransferase 1A10 ............................... 21 2.4 Conventional computer-aided drug design ............................................... 22 2.4.1 Molecular docking and scoring function ......................................... 23 2.4.2 Pharmacophore modeling .................................................................. 24 2.4.3 QSAR ..................................................................................................... 24 2.4.4 Similarity searching ............................................................................. 25 2.4.5 Prediction of ligand binding site ....................................................... 26 2.5 Simple coumarins as lead molecules ........................................................... 27 3 AIMS OF THE STUDY ........................................................................................... 33 4 METHODS ............................................................................................................... 34 4.1 Databases ......................................................................................................... 35 4.2 Ligand preparation ......................................................................................... 36 4.2.1 LigPrep (I, II, III, IV, V) ....................................................................... 36 4.2.2 ConfGen (III, IV) .................................................................................. 36 4.3 Negative image methods ............................................................................... 36 4.3.1 NIB VOIDOO/FLOOD (II) ................................................................ 36 4.3.2 Panther (I, III, IV, V) ............................................................................ 37 4.4 Similarity comparison .................................................................................... 38 4.4.1 ShaEP (II, III, IV) .................................................................................. 38 4.5 Molecular docking .......................................................................................... 38 4.5.1 GLIDE docking (II, IV) ........................................................................ 39 4.5.2 PLANTS docking (I, II, V) .................................................................. 40 4.6 Molecular dynamics simulations ................................................................. 40 4.6.1 NAMD (II) ............................................................................................ 40 4.7 Enrichment metrics ........................................................................................ 41 4.7.1 ROC AUC (II) ....................................................................................... 41 4.8 Modeling .......................................................................................................... 42 4.8.1 Homology modeling (V) ..................................................................... 42 4.9 Experimental methods ................................................................................... 43 4.9.1 Continuous spectrophotometric assay (I) ........................................ 43 4.9.2 Fluorescence polarization (II) ............................................................ 43 4.9.3 Reporter assay system (IV) ................................................................. 44 4.10 Illustrations ...................................................................................................... 45 5 RESULTS .................................................................................................................. 46 5.1 Coumarin scaffold as a lead compound (I, II, III, V) ................................. 46 5.1.1 Novel 3-phenylcoumarin derivatives as MAO inhibitors (I) ........ 46 5.1.2 Coumarin derivatives resembling 17(cid:451)-estradiol as ER(cid:450) ligands (II)…… ..................................................................................... 50 5.1.3 Building new inhibitors to block estradiol synthesis pathways using 3-phenylcoumarin derivatives (III) ........................................ 51 5.1.4 Selective 7-hydroxycoumarin derivatives as UGT1A10 substrates (V) ........................................................................................ 54 5.1.5 Selectivity of the coumarin derivatives (I, II, III, V) ....................... 55 5.2 Structure-based virtual screening of ROR(cid:452)t inverse agonists (IV) .......... 59 5.3 Homology modeling of UGT1A enzymes for designing selective 7-hydroxycoumarin based substrates (V) ................................................... 60 6 DISCUSSION ........................................................................................................... 64 6.1 Pharmacological potential of 3-phenylcoumarin derivatives .................. 64 6.2 Virtual screening ............................................................................................. 68 6.3 Homology modeling ...................................................................................... 68 7 CONCLUSIONS ...................................................................................................... 70 Acknowledgements ............................................................................................................ 71 REFERENCES .................................................................................................................. 75
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