56 Methods and Principles in Medicinal Chemistry Dömling Edited by Alexander Dömling Treating protein-protein interactions as a novel and highly promising class of drug targets, this volume introduces the underlying strategies step by step, from the biology of PPIs to biophysical and computational methods for their investigation. (Ed.) The main part of the book describes examples of protein targets for which small molecule modulators have been developed, covering such Protein–Protein diverse fields as cancer, autoimmune disorders and infectious diseases. Tailor-made for the practicing medicinal chemist, this ready reference includes a wide selection of case studies taken straight from the develop- ment pipeline of major pharmaceutical companies to illustrate the power Interactions in and potential of this approach. From the contents: G Prediction of intra- and inter-species protein-protein interactions Drug Discovery facilitating systems biology studies G Modulators of protein-protein interactions: the importance of three-dimensionality G Interactive technologies for leveraging the known chemistry of anchor residues G SH3 domains as drug targets G P53 MDM2 antagonists: towards non genotoxic anticancer Protein–Protein Interactions treatments in Drug Discovery Volume 56 G Inhibition of LFA-1/ICAM interaction for treatment of autoimmune diseases G The PIF-binding pocket of AGC kinases Series Editors: G Peptidic inhibitors of protein-protein interactions for cell adhesion R.Mannhold, receptors G The REPLACE strategy for generating non-ATP competitive H.Kubinyi, inhibitors of cell-cycle protein kinases G.Folkers and more Alexander Dömling studied Chemistry and Biology at the Technical University Munich, Germany. After obtaining his PhD under the supervision of Ivar Ugi, he spent a postdoctoral year at the Scripps Research Institute in La Jolla (USA) in the group of Nobel Laureate Barry Sharpless. In 2004 he performed his habilitation at the Technical University of Munich. Since 2006 he teaches and performs research at the University of Pittsburgh in the Department of Pharmacy with secondary appointments in Chemistry and Computational Biology. In 2010 he became full professor receiving his tenure in Pittsburgh. Since 2011 he is chairing the department of Drug Design at the University of Groningen/The Netherlands. Dr. Dömling is founder of several biotech companies, including Morphochem and Carmolex. His research centers around the discovery of antagonists of protein- protein interactions and other biologically active compounds in the therapeutic areas of oncology, infectious and neglected tropical diseases using “out-of-the-box” software tools and multicomponent reaction chemistries. www.wiley-vch.de Edited by Alexander D€omling Protein–Protein Interactions in Drug Discovery Related Titles Methods and Principles in Medicinal Chemistry Edited by R. Mannhold, H. Kubinyi, G. Folkers Editorial Board H. Buschmann, H. Timmerman, H. van de Waterbeemd, T. Wieland Previous Volumes of this Series Kalgutkar, Amit S. / Dalvie, Deepak / De Clercq, Erik (Ed.) Obach, R. Scott / Smith, Dennis A. Antiviral Drug Strategies Reactive Drug Metabolites 2011 2012 ISBN: 978-3-527-32696-9, Vol. 50 ISBN: 978-3-527-33085-0, Vol. 55 Klebl, Bert / Muller,€ Gerhard / Hamacher, Brown, Nathan (Ed.) Michael (Eds.) Bioisosteres in Medicinal Protein Kinases as Drug Chemistry Targets 2012 2011 ISBN: 978-3-527-33015-7, Vol. 54 ISBN: 978-3-527-31790-5, Vol. 49 Gohlke, Holger (Ed.) Sotriffer, Christoph (Ed.) Protein-Ligand Interactions Virtual Screening 2012 Principles, Challenges, and Practical ISBN: 978-3-527-32966-3, Vol. 53 Guidelines 2011 Kappe, C. Oliver / Stadler, Alexander / ISBN: 978-3-527-32636-5, Vol. 48 Dallinger, Doris Microwaves in Organic and Rautio, Jarkko (Ed.) Medicinal Chemistry Prodrugs and Targeted Second, Completely Revised and Delivery Towards Better ADME Enlarged Edition Properties 2012 2011 ISBN: 978-3-527-33185-7, Vol. 52 ISBN: 978-3-527-32603-7, Vol. 47 Smith, Dennis A. / Allerton, Charlotte / Smit, Martine J. / Lira, Sergio A. / Leurs, Kalgutkar, Amit S. / van de Waterbeemd, Rob (Eds.) Han / Walker, Don K. Chemokine Receptors as Drug Pharmacokinetics and Targets Metabolism in Drug Design 2011 Third, Revised and Updated Edition ISBN: 978-3-527-32118-6, Vol. 46 2012 ISBN: 978-3-527-32954-0, Vol. 51 Edited by Alexander D€omling Protein–Protein Interactions in Drug Discovery Series Editors All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and Prof. Dr. Raimund Mannhold publisher do not warrant the information contained Molecular Drug Research Group in these books, including this book, to be free of Heinrich-Heine-Universit€at errors. Readers are advised to keep in mind that Universit€atsstrasse 1 statements, data, illustrations, procedural details or 40225 Dusseldorf€ other items may inadvertently be inaccurate. Germany Library of Congress Card No.: applied for [email protected] British Library Cataloguing-in-Publication Data Prof. Dr. Hugo Kubinyi A catalogue record for this book is available from the Donnersbergstrasse 9 British Library. 67256 Weisenheim am Sand Bibliographic information published by the Deutsche Germany Nationalbibliothek [email protected] The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; Prof. Dr. Gerd Folkers detailed bibliographic data are available on the Collegium Helveticum Internet at < http:// dnb.d-nb.d e> . STW/ETH Zurich 8092 Zurich # 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Switzerland Boschstr. 12, 69469 Weinheim, Germany [email protected] All rights reserved (including those of translation into other languages). No part of this book may be Volume Editor reproduced in any form – by photoprinting, microfilm, or any other means – nor transmitted or Prof. Dr. Alexander D€omling translated into a machine language without written University of Groningen permission from the publishers. Registered names, School of Pharmacy trademarks, etc. used in this book, even when not Drug Design specifically marked as such, are not to be considered Antonius Deusinglaan 1 unprotected by law. 9713 AV Groningen Netherlands Composition Thomson Digital, Noida, India Printing and Binding Markono Print Media Pte Ltd, Cover Singapore Cut-away view of the co-crystal structure of an archetypical protein- protein interaction: the Cover Design Schulz Grafik-Design, Fugonheim€ tumor suppressor p53 and the oncogene Print ISBN: 978-3-527-33107-9 MDM2 (PDB ID 1YCR). The most deepest ePDF ISBN: 978-3-527-64823-8 buried p53 amino acid Trp23, anchoring the ePub ISBN: 978-3-527-64822-1 PPI, is shown in sticks presentation, the MDM2 mobi ISBN: 978-3-527-64821-4 receptor is shown as surface. Also shown the oBook ISBN: 978-3-527-64820-7 hydrogen bond between the Trp23 indole-NH and the receptor Leu54 carbonyl as green Printed in Singapore dotted line. The picture was rendered using Printed on acid-free paper PYMOL software. jV Contents List of Contributors XI Preface XV A Personal Foreword XVII 1 Protein–Protein Interactions: An Overview 1 Christian Ottman 1.1 Introduction 1 1.2 Role of PPIs in Human Physiology 2 1.3 Regulation of PPIs 3 1.4 Structural Features of PPI Interfaces 3 1.4.1 iNOS Homodimer 5 1.4.2 b-Catenin/Tcf4 Complex 5 1.4.3 LEDGF/HIV-IN Complex 6 1.4.4 HPV E1/E2 Complex 7 1.4.5 IFN-a/IFNAR Complex 8 1.4.6 TNF-a Trimer 9 1.5 Identification of PPI Inhibitors 10 1.6 Conclusions and Outlook 13 References 14 2 Prediction of Intra- and Interspecies Protein–Protein Interactions Facilitating Systems Biology Studies 21 Sylvia Schleker, Seshan Ananthasubramanian, Judith Klein-Seetharaman, and Madhavi K. Ganapathiraju 2.1 Introduction: Relevance of Interactome Studies to Disease and Drug Discovery 21 2.2 Our Current Knowledge of Interactomes Identified from Experiments is Incomplete 23 2.3 Reliability of Interactions Identified Experimentally 24 2.4 Computational Methods for PPI Prediction 27 2.4.1 Conservation of Gene Neighborhood 27 2.4.2 Gene Fusion 28 2.4.3 Sequence-Based Coevolution 28 VIj Contents 2.4.4 Phylogenetic Profiling 28 2.4.5 Gene Expression 29 2.4.6 Structural Similarity 29 2.4.7 Integration Approaches 29 2.5 Sources of Biological Data in Use to Predict PPIs 30 2.6 Survey of Current Interactomes 32 2.6.1 Human Intraspecies Interactomes 32 2.6.2 Bacteria Intraspecies Interactomes 37 2.6.2.1 High-Throughput Experimental Approaches to Identify Intraspecies Bacterial Interactions 37 2.6.2.2 Modeling Intraspecies Bacterial Interactions 39 2.6.3 Bacteria–Human Interspecies Interactomes 40 2.6.3.1 Experimental Approaches to Identify Bacteria–Human PPIs 40 2.6.3.2 Modeling Bacteria–Human PPIs 40 2.6.4 Non-PPI Intraspecies Bacterial and Bacteria–Human Interspecies Interactome Models 41 2.6.5 Virus–Human Interspecies Interactomes 42 References 43 3 Modulators of Protein–Protein Interactions: Importance of Three-Dimensionality 55 David C. Fry and Sung-Sau So 3.1 Introduction 55 3.2 Study 56 3.3 Discussion 58 3.4 Summary 61 References 61 4 A Leap into the Chemical Space of Protein–Protein Interaction Inhibitors 63 Bruno O. Villoutreix, C. Labbe, David Lagorce, Guillaume Laconde, and Olivier Sperandio 4.1 Introduction 63 4.2 Types of Interaction 64 4.3 Properties of the Interface 65 4.4 Orthosteric versus Allosteric Modulation 66 4.5 Leap into the iPPI Chemical Space 66 4.5.1 Seminal Works 66 4.5.2 Road to a Rationalization of the iPPI Chemical Space 67 4.6 Case Study 68 4.6.1 Visualizing the iPPI Chemical Space 70 4.6.2 iPPI versus ADME/Tox Properties 71 4.6.3 iPPI versus Aromaticity 75 4.6.4 iPPI versus Chemical Complexity 77 Contents jVII 4.6.5 iPPI versus Molecular Shape 77 4.6.6 iPPI versus Potency 79 4.7 Conclusions 80 References 81 5 Interactive Technologies for Leveraging the Known Chemistry of Anchor Residues to Disrupt Protein Interactions 85 Carlos J. Camacho, David R.