Christoph Sotriffer - Virtual Screening: Principles, Challenges, and Practical Guidelines (Methods and Principles in Medicinal Chemistry) volume 48

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:

Rautio, Jarkko (Ed.)

Prodrugs and Targeted Delivery

Towards Better ADME Properties

2011

ISBN: 978-3-527-32603-7

Vol. 47

Smit, Martine J. / Lira, Sergio A. / Leurs,

Rob (Eds.)

Chemokine Receptors as Drug Targets

2011

ISBN: 978-3-527-32118-6

Vol. 46

Ghosh, Arun K. (Ed.)

Aspartic Acid Proteases as Therapeutic Targets

2010

ISBN: 978-3-527-31811-7

Vol. 45

Ecker, Gerhard F. / Chiba, Peter (Eds.)

Transporters as Drug Carriers

Structure, Function, Substrates

2009

ISBN: 978-3-527-31661-8

Vol. 44

Faller, Bernhard / Urban, Laszlo (Eds.)

Hit and Lead Profiling

Identification and Optimization of Drug-like Molecules

2009

ISBN: 978-3-527-32331-9

Vol. 43

Sippl, Wolfgang / Jung, Manfred (Eds.)

Epigenetic Targets in Drug Discovery

2009

ISBN: 978-3-527-32355-5

Vol. 42

Todeschini, Roberto / Consonni, Viviana

Molecular Descriptors for Chemoinformatics

Volume I: Alphabetical Listing /

Volume II: Appendices, References

2009

ISBN: 978-3-527-31852-0

Vol. 41

van de Waterbeemd, Han / Testa,

Bernard (Eds.)

Drug Bioavailability

Estimation of Solubility, Permeability, Absorption and Bioavailability

Second, Completely Revised Edition

2008

ISBN: 978-3-527-32051-6

Vol. 40

Ottow, Eckhard / Weinmann, Hilmar (Eds.)

Nuclear Receptors as Drug Targets

2008

ISBN: 978-3-527-31872-8

Vol. 39

Vaz, Roy J. / Klabunde, Thomas (Eds.)

Antitargets

Prediction and Prevention of Drug Side Effects

2008

ISBN: 978-3-527-31821-6

Vol. 38

Series Editors

Prof. Dr. Raimund Mannhold

Molecular Drug Research Group

Heinrich-Heine-Universitt

Universittsstrasse 1

40225 Dsseldorf

Germany

Prof. Dr. Hugo Kubinyi

Donnersbergstrasse 9

67256 Weisenheim am Sand

Germany

Prof. Dr. Gerd Folkers

Collegium Helveticum

STW/ETH Zurich

8092 Zurich

Switzerland

Volume Editor

Prof. Dr. Christoph Sotriffer

University of Wrzburg

Institute of Pharmacy and Food Chemistry

Am Hubland

97074 Wrzburg

Germany

Cover Description

Virtual screening is a process of hierarchical filtering, searching compounds from chemical space that are suitable for interaction with targets from biological space. The illustrated hit stems from a virtual screening study conducted by Brenk et al. (2003), which is discussed in chapters 10 and 12 of this book. (Support by Dr. Matthias Zentgraf in preparation of this graph is gratefully acknowledged.)

All books published by Wiley-VCH are carefully produced. Nevertheless, authors, editors, and publisher do not warrant the information contained in these books, including this book, to be free of errors. Readers are advised to keep in mind that statements, data, illustrations, procedural details or other items may inadvertently be inaccurate.

Library of Congress Card No.: applied for

British Library Cataloguing-in-Publication Data

A catalogue record for this book is available from the British Library.

Bibliographic information published by the Deutsche Nationalbibliothek

The Deutsche Nationalbibliothek lists this publication in the Deutsche Nationalbibliografie; detailed bibliographic data are available on the Internet at http://dnb.d-nb.de .

2011 WILEY-VCH Verlag & Co. KGaA, Boschstr. 12, 69469 Weinheim, Germany

All rights reserved (including those of translation into other languages). No part of this book may be reproduced in any form by photoprinting, microfilm, or any other means nor transmitted or translated into a machine language without written permission from the publishers. Registered names, trademarks, etc. used in this book, even when not specifically marked as such, are not to be considered unprotected by law.

Typesetting Thomson Digital, Noida, India

Printing and Binding ???

Cover Design Schulz Grafik-Design, Fugnheim

Printed in the Federal Republic of Germany

Printed on acid-free paper

ISBN: 978-3-527-32636-5

Dedicated with love to Edith, Mathilde, Jonathan, and Therese

List of Contributors

ric Arnoult

Janssen-Cilag S.A.

Campus de Maigremont

BP 615

27106 Val de Reuil Cedex

France

Jrgen Bajorath

Rheinische Friedrich-Wilhelms

Universitt

Department of Life Science Informatics

B-IT, LIMES Program Unit Chemical

Biology and Medicinal Chemistry

Dahlmannstr. 2

53113 Bonn

Germany

Daniele Bemporad

Janssen Pharmaceutical N.V.

Johnson & Johnson Pharmaceutical

Research and Development

Turnhoutseweg 30

2340 Beerse

Belgium

Markus Boehm

Pfizer Pharma Therapeutics R & D

Worldwide Medicinal Chemistry

Eastern Point Rd

Groton, CT 06340

USA

Christophe Buyck

Tibotec BVBA

Turnhoutseweg 30

2340 Beerse

Belgium

Amedeo Caflisch

University of Zurich

Department of Biochemistry

Winterthurerstrasse 190

8057 Zurich

Switzerland

Claudio N. Cavasotto

University of Texas at Houston

School of Biomedical Informatics

7000 Fannin, Ste. 600

Houston, TX 77030

USA

Jason C. Cole

University of Cambridge

Crystallographic Data Centre

12 Union Road

Cambridge CB2 1EZ

UK

Maxwell D. Cummings

Tibotec BVBA

Turnhoutseweg 30

2340 Beerse

Belgium

Preface

In an early definition by Walters, Stahl, and Murcko [1], virtual screening (VS) is described as the Use of high-performance computing to analyze large databases of chemical compounds in order to identify possible drug candidates.

Virtual screening has become an integral part of the drug discovery process. It has largely been a numbers game focusing on questions like how can we filter down the enormous chemical space of over 1060 conceivable compounds to a manageable number that can be synthesized or purchased and tested. Although filtering the entire chemical universe might be a fascinating question, more practical VS scenarios focus on designing and optimizing targeted combinatorial libraries and enriching libraries of available compounds from in-house compound repositories or vendor offerings.

The purpose of virtual screening is to come up with hits of novel chemical structure that bind to the macromolecular target of interest. Thus, success of a virtual screen is defined in terms of finding interesting new scaffolds rather than many hits. Interpretations of VS accuracy should therefore be considered with caution. Low hit rates of interesting scaffolds are clearly preferable over high hit rates of already known scaffolds.

In a logical and didactic way, this volume is organized in four parts covering principles, challenges, practical guidelines, and case studies under different scenarios. Chapters of Part One are dedicated to virtual screening of chemical space, processing of small molecule databases for virtual screening, ligand-based and target-based virtual screening, virtual screening with 3D pharmacophore models, and docking methods. Challenges discussed in Part Two comprise affinity prediction, fragment-based approaches, handling of protein flexibility, as well as consideration of water and solvation effects, as well as parallel virtual screening for compound profiling and prediction of off-target effects. Finally, strategies, recommendations, and caveats for applying virtual screening methodology are given and many success stories are described.