COMPUTATIONAL CHEMOGENOMICS This page intentionally left blank COMPUTATIONAL CHEMOGENOMICS edited by Edgar Jacoby CRC Press Taylor & Francis Group 6000 Broken Sound Parkway NW, Suite 300 Boca Raton, FL 33487-2742 © 2013 by Taylor & Francis Group, LLC CRC Press is an imprint of Taylor & Francis Group, an Informa business No claim to original U.S Government works Version Date: 20131121 International Standard Book Number-13: 978-981-4411-40-0 (eBook - PDF) This book contains information obtained from authentic and highly regarded sources Reasonable efforts have been made to publish reliable data and information, but the author and publisher cannot assume responsibility for the validity of all materials or the consequences of their use The authors and publishers have attempted to trace the copyright holders of all material reproduced in this publication and apologize to copyright holders if permission to publish in this form has not been obtained If any copyright material has not been acknowledged please write and let us know so we may rectify in any future reprint Except as permitted under U.S Copyright Law, 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 Visit the Taylor & Francis Web site at http://www.taylorandfrancis.com and the CRC Press Web site at http://www.crcpress.com Contents Preface Chemogenomics Approaches for the Quantitative Comparison of Biological Targets Herbert Koeppen and Michael Bieler 1.1 Introduction 1.2 Target-Based Similarity Methods 1.3 Ligand-Based Target Comparison 1.3.1 Chemocentric Approaches 1.3.2 Chemoprint Approaches 1.4 The Impact of Data Quality on Chemogenomics 1.4.1 Experimental Variations and Errors 1.4.2 Thresholds and Cutoff Values 1.4.3 The Dataset Composition 1.4.4 The Lack of Data Completeness 1.4.5 The Applicability Domain 1.5 Applications 1.6 Conclusions Considerations on the Drug-Like Chemical Space Jean-Louis Reymond, Lars Ruddigkeit, and Mahendra Awale 2.1 Introduction 2.2 The Chemical Space 2.2.1 Compound Databases 2.2.2 The Chemical Universe Database 2.2.3 Virtual Combinatorial Libraries 2.2.4 Evolutionary Algorithms 2.3 Visualization 2.4 Drug Likeness 2.4.1 Small Is Beautiful! 2.4.2 Analysis of Compound Databases 2.5 Where to Find New Drugs? 2.6 Conclusion and Outlook xi 1 9 14 19 20 21 22 23 24 26 29 39 40 40 41 42 44 44 46 49 50 52 54 57 vi Contents Chemogenomic Protein-Family Methods in Drug Discovery: Profile-QSAR and Kinase-Kernel Prasenjit Mukherjee and Eric Martin 3.1 Introduction 3.2 Chemogenomics and Kinase Family Methods 3.3 Profile-QSAR and Other Affinity Fingerprint Methods 3.3.1 Profile-QSAR Theory 3.3.2 Profile-QSAR Biochemical Models 3.3.3 Profile-QSAR Cellular Models 3.3.4 Profile-QSAR Selectivity Modeling 3.4 Kinase-Kernel 3.4.1 SAR Similarity vs Sequence Similarity 3.4.2 Optimization of the Kinase-Kernel 3.4.3 Primary Interpolation Weights Optimized by Mixture Design 3.4.4 Genetic Algorithm Optimization of Binding Site Residue Selection and Neighbor Count 3.4.5 Most Relevant Residues 3.4.6 Performance Comparison 3.4.7 External Validation 3.5 Protein-Family Virtual Screening 3.6 Summary and Conclusions Virtual Screening and Target Fishing for Natural Products Using 3D Pharmacophores Gerhard Wolber and Judith M Rollinger 4.1 Introduction 4.1.1 Multitargeted Nature of Natural-Based Compounds 4.1.2 Daunting Challenges in Handling of Natural Products 4.1.3 Advent of Data Mining Tools and in silico Methods 4.2 Natural-Product Characteristics Compared to Synthetic Compounds 4.3 3D Pharmacophore Models for Virtual Screening and Activity Profiling 65 65 67 69 71 73 74 79 80 84 85 86 89 90 94 96 100 109 117 117 119 119 120 121 122 Contents 4.4 4.5 4.6 4.7 Resources for in silico Discovery of Natural Products (Databases) Success Stories of Pharmacophore-Based Virtual Screening for Natural-Product Discovery Activity Profiling for Identifying Novel Biological Activities of Natural Products Conclusion Computational Analysis of Ligand-Binding Pockets Felix Reisen and Gisbert Schneider 5.1 Introduction 5.2 Software for Binding Site Comparison 5.3 Mathematical Models 5.3.1 Alignment-Based Methods 5.3.2 Vector-Based Representations 5.4 Protein Structure Representation 5.4.1 Group I Methods 5.4.2 Group II Methods 5.4.3 Group III Methods 5.5 PoLiMorph 5.6 Comparison of Software Performance 5.7 Conclusions Binding Site Similarity Search to Identify Novel Target–Ligand Complexes Didier Rognan 6.1 Why Focusing on Binding Sites 6.2 Sequence-Based Approaches 6.2.1 From Target Sequences to Ligands 6.2.2 From Target Sequences to Pharmacophores to Ligands 6.2.3 Simultaneous Usage of Target Sequence and Ligand Descriptors 6.3 Structure-Based Approaches 6.3.1 Pocket Detection and Comparisons 6.3.2 Drug Repurposing by Binding Site 3D Similarity Search 6.4 Conclusions 125 127 129 133 141 141 142 145 145 148 150 150 154 156 158 161 162 171 171 174 174 177 178 179 181 182 186 vii viii Contents ChemProt: A Disease Chemical Biology Database Olivier Taboureau and Tudor I Oprea 7.1 Introduction 7.2 Bioactivity and Biological Repositories 7.2.1 Bioactivity Databases 7.2.2 Biological Databases 7.3 Prediction Methods 7.4 The ChemProt Server: Instructions and Output 7.5 Perspectives on ChemProt Scientific Requirements for the Next-Generation Semantic Web-Based Chemogenomics and Systems Chemical Biology Molecular Information System OPS Edgar Jacoby, Kamal Azzaoui, Stefan Senger, Emiliano Cuadrado Rodríguez, Mabel Loza, Antony J Williams, Victor de la Torre, Jordi Mestres, Olivier Taboureau, Matthias Rarey, Christine Chichester, Niklas Blomberg, Lee Harland, Barbara Zdrazil, Marta Pinto, and Gerhard Ecker 8.1 Introduction 8.2 Methods 8.3 Results 8.3.1 Provide All Oxidoreductase Inhibitors Active