In Silico Technologies in Drug Target Identification and Validation © 2006 by Taylor and Francis Group, LLC Drug Discovery Series Series Editor Andrew Carmen Johnson & Johnson PRD, LLC San Diego, California, U.S.A. 1. Virtual Screening in Drug Discovery, edited by Juan Alvarez and Brian Shoichet 2. Industrialization of Drug Discovery: From Target Selection Through Lead Optimization, edited by Jeffrey S. Handen, Ph.D. 3. Phage Display in Biotechnology and Drug Discovery, edited by Sachdev S. Sidhu 4. G Protein-Coupled Receptors in Drug Discovery, edited by Kenneth H. Lundstrom and Mark L. Chiu 5. Handbook of Assay Development in Drug Discovery, edited by Lisa K. Minor 6. In Silico Technologies in Drug Target Identification and Validation, edited by Darryl León and Scott Markel © 2006 by Taylor and Francis Group, LLC Drug Discovery Series/6 In Silico Technologies in Drug Target Identification and Validation Edited by Darryl León Scott Markel Boca Raton London New York CRC is an imprint of the Taylor & Francis Group, an informa business © 2006 by Taylor and Francis Group, LLC CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2006 by Taylor and Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S. Government works Printed in the United States of America on acid-free paper 10 9 8 7 6 5 4 3 2 1 International Standard Book Number-10: 1-57444-478-6 (Hardcover) International Standard Book Number-13: 978-1-57444-478-0 (Hardcover) Library of Congress Card Number 2006005722 This book contains information obtained from authentic and highly regarded sources. Reprinted material is quoted with permission, and sources are indicated. A wide variety of references are listed. Reasonable efforts have been made to publish reliable data and information, but the author and the publisher cannot assume responsibility for the validity of all materials or for the conse- quences of their use. No part of this book may be reprinted, reproduced, transmitted, or utilized in any form by any electronic, mechanical, or other means, now known or hereafter invented, including photocopying, microfilming, and recording, or in any information storage or retrieval system, without written permission from the publishers. For permission to photocopy or use material electronically from this work, please access www. copyright.com (http://www.copyright.com/) or contact the Copyright Clearance Center, Inc. (CCC) 222 Rosewood Drive, Danvers, MA 01923, 978-750-8400. CCC is a not-for-profit organization that provides licenses and registration for a variety of users. For organizations that have been granted a photocopy license by the CCC, a separate system of payment has been arranged. Trademark Notice: Product or corporate names may be trademarks or registered trademarks, and are used only for identification and explanation without intent to infringe. Library of Congress Cataloging-in-Publication Data In silico technologies in drug target identification and validation / edited by Dar- ryl León and Scott Markel. p. ; cm. Includes bibliographical references and index. ISBN-13: 978-1-57444-478-0 (Hardcover : alk. paper) ISBN-10: 1-57444-478-6 (Hardcover : alk. paper) 1. Drug development. 2. Drug development-Computer simulation. [DNLM: 1. Drug Delivery Systems-methods. 2. Chemistry, Pharmaceutical. 3. Computational Biology. WB 340 I35 2006] I. León, Darryl. II. Markel, Scott. RM301.25.I48 2006 615’.19--dc22 2006005722 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com © 2006 by Taylor and Francis Group, LLC Foreword When asked to write the foreword for this book in the early phases of planning, we wondered how much of the planned scope and depth would be possible to achieve. León and Markel had selected a broad range of possible topics, which became “must use” tools and technologies in the early drug-development process. In addition, they included topics about emerging technologies that have not made it to a broader audience and user community today, but have the potential to become essential in the next few years. They had compiled a list of world-renowned experts from the industrial sector as well as from research organizations and universities, asked them to provide a chapter, and then ably shepherded the process to completion. León and Markel are both well-known experts in the field of life science infor- matics and both have collected in-depth knowledge and expert insight while affiliated with academic institutions and commercial entities. They have an outstanding knowl- edge about tools and technologies used and applied in the life science informatics area. In industry, they both played a major role in the architectural direction and the scientific design and content of major software solutions. In addition, they are involved in teaching bioinformatics and in the establishment and further development of standards. After having the result in hand, we must say that it is a remarkable collection of in-depth chapters covering almost all major in silico techniques used today in the early drug development process. Each chapter is a valuable information source for the reader, whether an expert in the field, a user of the technology, or simply a researcher interested in understanding some of the technologies lying outside of his or her direct expertise. Over the last 20 years, and especially in the last years of the 20th century, we saw some hype and “dot-com” behavior in the field of computational biology. This has certainly “cleared” by now, and much of the hype and promises have been taken down to more solid ground. We saw a remarkable expansion in the use of compu- tational methods, and completely new applications areas have emerged. We can foresee that this will be the case for future decades. Undoubtedly, computational methods and technologies are core prerequisites in today’s drug-development pro- cess, and efficient and innovative use of these technologies will be a key success factor for the development of drugs in the future. The application areas include the basic information technology challenges (e.g., data acquisition, storage, and retrieval), more advanced topics (e.g., analysis pipelines), and emerging technologies (e.g., text mining and pathway analysis). This book will prepare the reader perfectly for the different “-omics” data floods, which we will face in the coming years. We hope you will have the same pleasure with the book as we have had. Dr. Reinhard Schneider Dr. Hartmut Voss Heidelberg, Germany © 2006 by Taylor and Francis Group, LLC Preface In 2004, Merck voluntarily withdrew the arthritis medication Vioxx® (Rofecoxib) from the worldwide market because patients taking it were observed to have an increased risk for heart attack and stroke. In the months that followed, additional COX-2 selective drugs were flagged as having serious side effects. These concerns about prescription drugs have made the pharmaceutical industry more focused on designing highly selective medications. In the current drug discovery process, select- ing the appropriate drug target can be as important as optimizing the chemical entity that binds to that target. Today, identifying and validating a potential drug target involves not only numer- ous well-designed experiments, but also the incorporation of several in silico approaches. These in silico analyses are often predictive, offering cheaper and faster alternatives to in vitro or in vivo procedures. This book addresses the in silico tech- nologies used in target identification and validation by describing how the available computational tools and databases are used within each step. The book is divided into four main sections. The first section addresses target identification and covers the areas of pattern matching, functional annotation, poly- morphisms, and mining gene expression data. The second section covers target validation, which includes text mining, pathways, molecular interactions, subcellular localization, and protein structures. The third section focuses on recent trends such as comparative genomics, pharmacogenomics, and systems biology. The final section discusses computational infrastructure resources needed to support target identifica- tion and validation, including database management, bioIT hardware and architec- ture, data pipelining, and ontologies. We hope that many people from various scientific and computational back- grounds will find this book useful. © 2006 by Taylor and Francis Group, LLC Editors Darryl León, Ph.D., is currently director of bioinformatics marketing at SciTegic in San Diego, California, where he provides the vision and software requirements for bioinformatics-related products. He is also on the Bioinformatics Advisory Com- mittee for the University of California San Diego Extension. Previously, he was director of life sciences at LION Bioscience, and was a bioinformatics scientist at NetGenics, DoubleTwist, and Genset. He was a faculty member at California Poly- technic State University, San Luis Obispo, and has authored several papers. He is a co-author, with Scott Markel, of Sequence Analysis in a Nutshell: A Guide to Common Tools and Databases. He has also taught at the University of California Santa Cruz Extension and at other colleges in northern California. Dr. Leon received his Ph.D. in biochemistry from the University of California–San Diego, and he did his postdoctoral research at the University of California–Santa Cruz. Scott Markel, Ph.D., is the principal bioinformatics architect at SciTegic, a division of Accelrys. In this role he is responsible for the design and implementation of SciTegic’s bioinformatics products. He is a member of the Board of Directors of the International Society for Computational Biology. He was most recently a research fellow and principal software architect at LION Bioscience, where he was responsible for providing architectural direction in the development of software for the life sciences, including the use and development of standards. He was a member of the Board of Directors of the Object Management Group and co-chair of the Life Sciences Research Domain Task Force.