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A Computational Study of the Substrate Conversion and Selective Inhibition of Aldosterone Synthase

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A computational study of the substrate conversion and selective inhibition of aldosterone synthase Citation for published version (APA): Roumen, L. (2008). A computational study of the substrate conversion and selective inhibition of aldosterone synthase. Technische Universiteit Eindhoven. https://doi.org/10.6100/IR637195 DOI: 10.6100/IR637195 Document status and date: Published: 01/01/2008 Document Version: Publisher’s PDF, also known as Version of Record (includes final page, issue and volume numbers) Please check the document version of this publication: • A submitted manuscript is the version of the article upon submission and before peer-review. There can be important differences between the submitted version and the official published version of record. People interested in the research are advised to contact the author for the final version of the publication, or visit the DOI to the publisher's website. • The final author version and the galley proof are versions of the publication after peer review. • The final published version features the final layout of the paper including the volume, issue and page numbers. Link to publication General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal. If the publication is distributed under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license above, please follow below link for the End User Agreement: www.tue.nl/taverne Take down policy If you believe that this document breaches copyright please contact us at: [email protected] providing details and we will investigate your claim. Download date: 06. Oct. 2021 A Computational Study of the Substrate Conversion and Selective Inhibition of Aldosterone Synthase The cover illustrates my eclectic interpretation of this research project. A catalogue record is available from the Eindhoven University of Technology Library. ISBN: 978-90-386-1365-9 Copyright ©2008 by L. Roumen All rights reserved. No part of this book may be reproduced, stored in a database or retrieval system, or published, in any form or in any way, electronically, mechanically, by print, photoprint, microfilm or any other means without prior written permission of the author. Cover design: K. Pieterse, L. Roumen Printed by PrintPartners Ipskamp, Enschede, The Netherlands This research was financially supported by the Dutch Technology Foundation STW, applied science division of NOW and the Technology Program of the Ministry of Economic Affairs. Grant Number MFA 6504. A Computational Study of the Substrate Conversion and Selective Inhibition of Aldosterone Synthase PROEFSCHRIFT ter verkrijging van de graad van doctor aan de Technische Universiteit Eindhoven, op gezag van de Rector Magnificus, prof.dr.ir. C.J. van Duijn, voor een commissie aangewezen door het College voor Promoties in het openbaar te verdedigen op woensdag 1 oktober 2008 om 16.00 uur door Luc Roumen geboren te Geldrop Dit proefschrift is goedgekeurd door de promotor: prof.dr. P.A.J. Hilbers Copromotor: dr. J.J.R.M. Hermans Table of Contents Chapter 1 Aldosterone Synthase inhibitors, a new treatment option for heart failure?........... 1 1.1 Heart Failure................................................................................................................................... 2 1.2 The Renin Angiotensin Aldosterone System.................................................................................. 2 1.3 Heart failure treatment.................................................................................................................... 3 1.4 Aldosterone Biosynthesis ............................................................................................................... 4 1.5 Starting Structures.......................................................................................................................... 5 1.6 Aim and Scope of this Thesis......................................................................................................... 7 Chapter 2 Homology Modelling............................................................................................ 11 2.1 Introduction................................................................................................................................... 12 2.2 Cytochrome P450 enzymes ......................................................................................................... 12 2.2.1 Nomenclature and generic function ..................................................................................... 12 2.2.2 Structural Architecture ......................................................................................................... 13 2.3 Homology Modelling..................................................................................................................... 17 2.4 Homology Models for CYP11B1 and CYP11B2........................................................................... 19 2.4.1 Modelling Criteria ................................................................................................................. 20 2.4.2 Multiple Sequence Alignment .............................................................................................. 21 2.4.3 Template Selection .............................................................................................................. 24 2.4.4 Template Construction......................................................................................................... 26 2.4.5 Additional Modelling Criteria: Point Mutants ........................................................................ 27 2.5 Hypothesis: Steric Aspects Play an Important Role in Substrate Conversion.............................. 28 2.6 Construction of CYP11B Models.................................................................................................. 29 2.7 Results and Discussion ................................................................................................................ 30 2.7.1 Model quality assessment.................................................................................................... 31 2.7.2 CYP11B1 and CYP11B2 model active site differences ....................................................... 36 2.7.3 Protein - Substrate interactions............................................................................................ 36 2.7.3.1 DOC............................................................................................................................. 39 2.7.3.2 18OH-DOC .................................................................................................................. 39 2.7.3.3 B and 18OH-B ............................................................................................................. 40 2.7.4 Triple-Mutant Influence ........................................................................................................ 40 2.7.5 Proposed Synthesis Mechanism of Aldosterone ................................................................. 40 2.8 Conclusions .................................................................................................................................. 41 Chapter 3 Molecular Dynamics ............................................................................................ 47 3.1 Molecular Dynamics ..................................................................................................................... 48 3.2 Force fields ................................................................................................................................... 48 3.3 Molecular Dynamics of hCYP11B1 and hCYP11B2..................................................................... 49 3.4 Molecular Dynamics Settings ....................................................................................................... 50 3.5 Results and Discussion ................................................................................................................ 51 3.5.1 Protein Structure Stability .................................................................................................... 51 3.5.2 Protein-Ligand Interactions .................................................................................................. 53 3.6 Conclusions .................................................................................................................................. 58 Chapter 4 Molecular Docking............................................................................................... 61 4.1 Molecular Docking........................................................................................................................ 62 4.1.1 GOLD................................................................................................................................... 63 4.1.2 Scoring Functions ................................................................................................................ 63 4.2 Prediction of Binding Affinity........................................................................................................
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