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The Human Histamine H3-Receptor: Amolecular Modelling Study of a G-Protein Coupled Receptor

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The Human Histamine H3-Receptor: Amolecular Modelling Study of a G-Protein Coupled Receptor THE HUMAN HISTAMINE H3-RECEPTOR: AMOLECULAR MODELLING STUDY OF A G-PROTEIN COUPLED RECEPTOR Inaugural-Dissertation zur Erlangung des Doktorgrades der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf vorgelegt von Birgit Schlegel aus Linz, Österreich Düsseldorf 2005 Gedruckt mit der Genehmigung der Mathematisch-Naturwissenschaftlichen Fakultät der Heinrich-Heine-Universität Düsseldorf Referent: Prof. Dr. Dr. h.c. Hans-Dieter Höltje 1. Korreferent: Prof. Dr. Wolfgang Sippl 2. Korreferent: Prof. Dr. Thierry Langer Tag der mündlichen Prüfung: 18. Juli 2005 Part I regarding the molecular dynamics simulation of bovine rhodopsin has been published in the Journal of Molecular Modeling. The original publication of this part is available at www.springerlink.com. Die vorliegende Arbeit wurde von November 2001 bis Mai 2005 am Institut für Pharmazeutische Chemie der Heinrich-Heine-Universität Düsseldorf unter der Betreuung von Prof. Dr. W. Sippl und Prof. Dr. Dr. h.c. H.-D. Höltje angefertigt. Mein besonderer Dank gilt Prof. Dr. Dr. h.c. Hans-Dieter Höltje für die Aufnahme in seinen Arbeitskreis, die sehr guten Rahmenbedingungen, den Ansporn eigene wissenschaftliche Ideen zu verteidigen, sowie eine drei-dimensionale Sicht der Welt der Arzneistoffe, die ich während des Besuchs seiner Vorlesung erlangen konnte. Bei Prof. Dr. Wolfgang Sippl möchte ich mich für die sehr gute Betreuung bedanken, die mir den nötigen Freiraum gelassen hat, eigene Ideen umzusetzen, aber gleichzeitig die Arbeit durch unzählige Diskussionen, Anregungen und Vorschläge in eine erfolgversprechende Richtung gelenkt hat. Neben seinem enormen fachlichen Wissen durfte ich auch von den sehr guten Ressourcen seines Arbeitskreises in Halle profitieren, was viele Aspekte der Arbeit erst ermöglicht hat. Bei unserem Kooperationspartner Prof. Dr. Holger Stark möchte ich mich für die Überlassung des Datensatzes an H3-Liganden bedanken, der essentiell für die Anfertigung dieser Arbeit war. Contents 1 Introduction 1 1.1 General Introduction . 1 1.2 G-Protein Coupled Receptors . 1 1.2.1 Pharmaceutical Relevance and Classification . 1 1.2.2 Molecular Structure and Signal Transduction . 3 1.2.3 The Structure of Bovine Rhodopsin . 4 1.2.4 Agonists, Antagonists and Inverse Agonists . 6 1.3 Histamine . 6 1.4 The Histamine Receptor Family . 8 1.4.1 The Human H3-Receptor . 9 1.4.2 The Human H4-Receptor . 20 2 Methods 25 2.1 Generation of Homology Models . 25 2.1.1 Introduction . 25 2.1.2 Sequence Analysis Tools . 25 2.1.3 Sequence Structure Alignment . 30 2.1.4 Adding Amino Acid Side Chains . 30 2.1.5 Prediction of Protonation States . 30 2.1.6 Force Field Methods: Energy Minimisation and MD Simulations . 32 2.1.7 Model Evaluation . 36 2.2 Conformational Analysis of Ligand Molecules . 37 2.3 Ligand Superposition Techniques . 38 i 2.4 Analysis of Interaction Fields . 39 2.5 Ligand Docking . 40 2.6 Pharmacophore Models for Screening Structural Databases . 40 I Molecular Modelling Studies of Bovine Rhodopsin 43 3 Scope 45 4 Results 47 4.1 System Setups for the Simulation of Bovine Rhodopsin . 47 4.1.1 Generation of Model Structures of Bovine Rhodopsin . 47 4.1.2 Bovine Rhodopsin in a CCl4/Water Environment . 49 4.1.3 Bovine Rhodopsin in a DPPC/Water Environment . 51 4.1.4 Calculation of pKa-shifts of Titrable Amino Acid Residues . 53 4.2 Truncated versus Entire Protein Models . 54 4.3 Consideration of Internal Water Molecules . 55 4.4 CCl4/Water versus DPPC/Water Environment . 59 4.5 Choice of the Correct State of Protonation . 61 4.5.1 Calculation of pKa-shifts Using the UHBD Program.......... 61 4.5.2 MD Simulations Comparing Different States of Protonation for Residues D83/2.50, E122/3.37, and E181/4.70 . 63 4.6 Studying the Conformational Adaptations after Introduction of all-trans-Retinal 67 4.7 Simulation Setup for the Analysis of Interhelical Contacts . 69 5 Discussion 75 5.1 System Setup . 76 5.2 Effects of an N-terminal Truncation . 76 5.3 Effects of Internal Water Molecules . 77 5.4 Influence of the Simulation Environment . 80 5.5 Choice of Protonation States . 81 5.6 Conformational Adaptations after Introduction of all-trans-Retinal . 82 5.7 Deriving Interhelical Contacts as Potential Constraints in GPCR Simulations 84 ii II Molecular Modelling Study of the Human Histamine H3- Receptor 87 6 Scope 89 7 Results 91 7.1 Generation of a Homology Model of the Human Histamine H3-Receptor . 91 7.1.1 Sequence Analysis Tools . 91 7.1.2 Sequence Structure Alignment . 93 7.1.3 Placing Amino Acid Side Chains . 95 7.1.4 Simultaneous Side Chain and Ligand Placement . 101 7.2 MD Simulations of hH3R Models . 103 7.2.1 MD Simulations of Uncomplexed hH3R Models . 103 7.2.2 MD Simulation of Inverse Agonist/hH3R Complexes . 109 7.3 Model Validation via Screening of a Focused Database . 121 7.4 Application of the Generated Binding Pocket Conformation as Filter in HTS 127 7.5 Pharmacophore Based Screening . 131 7.6 The hH3R Binding Site, Suggested Structures and Implications for the hH4R 140 7.6.1 The hH3R Binding Site . 140 7.6.2 Suggested Structures for Experimental Testing . 144 8 Discussion 149 8.1 Generation of a Homology Model of the Human Histamine H3-Receptor and Comparison with other hH3R Models . 149 8.2 High Throughput Screening by Docking . 156 8.3 Pharmacophore Based Screening . 157 8.4 Analysis of the hH3R Binding Pocket . 160 8.4.1 Orientation of H3R Ligands in the Binding Pocket . 160 8.4.2 Species Differences for the H3R ................... 162 8.4.3 Agonism versus Inverse Agonism . 163 9 Summary 167 iii 10 Appendix 169 10.1 Force Field Terms . 169 10.1.1 Bonded Interactions . 169 10.1.2 Non-Bonded Interactions . 171 10.2 Example Parameter Input File for an MD Simulation in GROMACS . 172 10.3 One Letter Code for Amino Acids . 177 10.4 List of Abbreviations . 178 iv List of Tables 1.1 Main actions of histamine on histamine receptors. 9 1.2 A short overview on the hH3R......................... 10 1.3 A short overview on the hH4R......................... 21 2.1 Types of interactions considered in a force field. 33 2.2 Pharmacophoric features observed in ligand FUB833. 42 4.1 Survey over models of bovine rhodopsin herein described. 48 4.2 GROMACS parameters for the simulation setup of a model of bovine rhodopsin in a CCl4/water environment. 51 4.3 GROMACS parameters for the simulation setup of a model of bovine rhodopsin in a DPPC/water environment. 52 4.4 pKa-shifts for titrable sites in the retinal/opsin complex showing significant deviations from the expected protonation states in aqueous solution. 62 4.5 MSA around residue E122/3.37. 62 4.6 Frequencies of interhelical hydrogen bonds observed during the simulation of a model of bovine rhodopsin. 72 7.1 Pinpoints described by Baldwin et al. .................... 94 7.2 Sequence structure alignment of the hH3R sequence and the structure of bovine rhodopsin within TM5. 95 7.3 MSA of representatives of biogen aminergic GPCRs within helix 5. 96 7.4 Alignment of the hH3R sequence with bovine rhodopsin. 97 7.5 Residues included in the approach of “inverse” docking. 102 7.6 Interhelical contacts included as constraints in simulations of hH3R models. 105 v 10.1 Prediction of transmembrane regions in the sequence of the hH3R. 180 10.2 Prediction of secondary structure in the sequence of the hH3R........181 10.3 Prediction of transmembrane regions in the sequence of bovine rhodopsin. 182 10.4 Prediction of secondary structure in the sequence of bovine rhodopsin. 183 vi List of Figures 1.1 Important target families in the human genome. 2 1.2 Diagram of GPCR function. 4 1.3 Crystal structure of bovine rhodopsin. 5 1.4 Photocycle. 5 1.5 The two state model of receptor activity. 6 1.6 Tautomeric forms of histamine. 7 1.7 Metabolism of histamine. 8 1.8 Function of hH3R as an autoreceptor. 11 1.9 H3R agonists. 13 1.10 Imidazole-containing H3R inverse agonists. 14 1.11 Non-imidazole-containing H3R inverse agonists. 16 1.12 Slight modifications can determine if a compound is a (partial) agonist or inverse agonist. 17 1.13 Structurally similar compounds covering the entire range from full agonism to inverse agonism. 17 1.14 Unselective H4R ligands. 22 1.15 Selective H4R ligands. 22 2.1 Possible applications of protein homology models in the drug discovery process. 26 2.2 Flowchart of homology model generation. 27 2.3 Alignment scheme. 28 2.4 Scheme for a multiple sequence alignment generation. 29 2.5 Calculation of pKa-shifts by the UHBD program................ 32 vii 2.6 Bonded and non-bonded interactions included in a force field potential. 33 2.7 Energy minimisation. 34 2.8 Molecular dynamics simulation. 35 2.9 Concept of pharmacophores explained on hH3R ligand FUB833. 41 4.1 Snakeplot of bovine rhodopsin. 48 4.2 Equilibration of a CCl4/water box: course of potential energy and pressure. 49 4.3 Comparison of the CCl4 layer after equilibration with/out pressure coupling. 50 4.4 Model of bovine rhodopsin in a CCl4/water box. 51 4.5 Introduction of a hole into the DPPC bilayer. 52 4.6 Model of bovine rhodopsin in a DPPC/water box. 53 4.7 Effects of an N-terminal truncation on the position of helix 1. 54 4.8 Comparison of the effects of an N-terminal truncation in different membrane mimics. 55 4.9 Plot of RMSD and interhelical hydrogen bonds during a simulation of a model of bovine rhodopsin with internal water molecules.
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