Quick Guideline for Computational Drug Design (Revised Edition)

Bioinformatics allows researchers to answer biological questions with advanced computational methods which involves the application of statistics and mathematical modeling. Structural bioinformatics enables the prediction and analysis of 3D structures of macromolecules while Computer Aided Drug Designing (CADD) assists scientists to design effective active molecules against diseases. However, the concepts in structural bioinformatics and CADD can be complex to understand for students and educated laymen. This quick guideline is intended as a basic manual for beginner students and instructors involved in bioinformatics and computational chemistry courses. Readers will learn the basics of structural bioinformatics, primary and secondary analysis and prediction, structural visualization, structural analysis and molecular docking. The book provides the reader an easy to read summary of the tools and techniques in structural bioinformatics as well as their limitations. In this revised edition, the authors have updated information in a number of chapters with a specific focus on the section on protein structure visualization and evaluation. Additional information on protein-ligand interaction studies has also been provided in this new edition. Therefore, the book is a useful handbook for aspiring scholars who wish to learn the basic concepts in computational analysis of biomolecules. Cover 1 Title 2 Copyright 3 End User License Agreement 4 Contents 6 Foreword 11 Preface 13 CONSENT FOR PUBLICATION 14 CONFLICT OF INTEREST 14 ACKNOWLEDGEMENTS 14 Dedication 16 Introduction to Structural Bioinformatics 17 MOTIVATION 17 BIOINFORMATICS 17 Bioinformatics Approaches 18 Static 18 Dynamic 18 Structural Bioinformatics 18 Software and Tools 19 Open-source Bioinformatics Software 19 Web Services in Bioinformatics 19 Virtual Screening 19 Homology Modeling 19 Steps of Homology Modeling 20 Accuracy 20 Importance of Homology modeling 21 Homology Modeling Tools 21 UniProt KB 21 Structure Prediction Tools 23 Model Validation Tools 23 Sequence Analysis Tools 23 Model Visualization Tools 23 Virtual Screening and Docking 23 Recent Advancements in Computational Drug Design 24 REFERENCES 25 Protein Primary Sequence Analysis 28 MOTIVATION 28 PROTPARAM EXPASY 29 Introduction 29 Brief Instructions 29 Requirements 29 Input 29 Sequence Submission 29 RESULTS INTERPRETATION 30 CONCLUSION 31 LIMITATIONS OF PRIMARY SEQUENCE ANALYSES 31 ProtParam Expassy 31 REFERENCE 32 Secondary Structure Analyses 33 MOTIVATION 33 SECONDARY STRUCTURE OF PROTEINS 33 PROFUNC 34 Brief Instructions 34 Requirements 34 Input 34 Sequence Submission 35 Accessing of Data 35 LIMITATIONS OF SECONDARY STRUCTURE ANALYSES TOOLS 35 ProFunc 35 REFERENCES 36 3D Structure Prediction 37 MOTIVATION 37 STRUCTURE PREDICTION TOOLS 38 PHYRE2 38 Introduction 38 Brief Instructions 38 Requirements 39 Input 39 Sequence Submission 39 RESULTS INTERPRETATION (RESULTS SCREEN) 39 Secondary Structure and Disorder Prediction 40 Domain Analysis 41 Detailed Template Information 41 Alignment View 41 CONCLUSION 42 I-TASSER 42 Introduction 42 Brief Instructions 42 Requirements 42 Input 42 Sequence Submission 42 Accessing Data 43 RESULTS INTERPRETATION (OUTPUT) 43 Structure Prediction 43 Top 10 Threading Templates Used by I-TASSER 43 Top 5 Final Model Predicted by I-TASSER 44 Structurally Closely Related Protein 45 Ligand Binding Site 47 CONCLUSION 47 RaptorX 47 Introduction 47 Brief Instructions 47 Requirements 48 Input 48 Sequence Submission 48 Accessing Data 48 RESULTS INTERPRETATION (OUTPUT) 49 Input Sequence and Domain Partition 49 Prediction Results 50 Detailed Prediction Results 50 SWISS-MODEL 50 Introduction 51 Brief Instructions 51 Requirements 51 Input 51 Sequence Submission 51 RESULTS INTERPRETATION (RESULTS SCREEN) 52 Summary 52 Templates 53 Models 53 CONCLUSION 53 3D-JIGSAW 53 Introduction 53 Brief Instructions 54 Requirements 54 Input 54 Sequence Submission 54 Accessing Data 54 RESULTS INTERPRETATION 54 CONCLUSION 54 INTFOLD2 55 Introduction 55 Brief Instructions 55 Requirements 55 Input 55 Sequence Submission 55 Accessing Data 56 RESULTS INTERPRETATION (OUTPUT) 56 CONCLUSION 56 HHPRED 57 Introduction 57 Brief Instructions 57 Requirements 57 Input 57 Sequence Submission 57 Accessing Data 58 RESULTS INTERPRETATION (OUTPUT) 59 CONCLUSION 59 M4T 59 Introduction 59 Brief Instructions 59 Requirements 59 Input 59 Sequence Submission 59 Accessing Data 60 RESULTS INTERPRETATION (OUTPUT) 61 CONCLUSION 61 MODELLER 61 Introduction 61 Downloading and Installation 61 Modeling Steps 62 Searching for Structures Related to PSEN2 62 BLAST (BASIC LOCAL ALIGNMENT SEARCHING TOOL) 63 Template PDB File 64 Aligning PSEN2 with the Template 65 Model Building 67 LIMITATIONS OF STRUCTURE PREDICTION TOOLS 68 Phyre2 68 I-Tasser 68 RaptorX 69 Swiss-model 69 3D-Jigsaw 69 Intfold2 69 M4T 69 Modeller 69 REFERENCES 71 Protein 3D Structure Assessment, Evaluation, and Validation 73 MOTIVATION 73 MODEL EVALUATION TOOLS 73 ERRAT 74 Introduction 74 Brief Instructions 74 Requirements 74 Input 74 Sequence Submission 75 RESULTS INTERPRETATION (OUTPUT) 76 CONCLUSION 76 RAMPAGE 76 Introduction 76 Brief Instructions 76 Requirements 77 Input 77 Sequence Submission 77 RESULTS INTERPRETATION 77 CONCLUSION 77 ANOLEA 77 Introduction 77 Brief Instructions 78 Requirements 78 Input 78 RESULTS INTERPRETATION 78 CONCLUSION 79 MOL PROBITY 79 Introduction 79 Brief Instructions 80 Requirements 80 Input 80 RESULTS INTERPRETATION 81 CONCLUSION 81 VERIFY 3D 81 Introduction 81 Brief Instructions 81 Requirements 81 Input 81 Sequence Submission 82 RESULTS INTERPRETATION 83 CONCLUSION 84 PDBSUM GENERATE 84 Introduction 84 Brief Instructions 84 Requirements 85 Input 85 Sequence Submission 85 Accessing Data 85 RESULTS INTERPRETATION 85 Output 86 Customization of Plots 86 LIMITATIONS OF STRUCTURE EVALUATION TOOLS ERRAT 86 Rampage 86 Verify3D 87 Pdbsum 87 REFERENCES 88 Ligand-Based Computational Molecular Docking Analysis 89 INTRODUCTION 89 Brief Instruction: MOE (Molecular Operating Environment) 90 REFERENCES 101 Protein-Ligand Interactions 106 MOTIVATION 106 Molecular Operating Environment (MOE) 107 Protein-Ligand Complex 107 3D Structure Visualization through MOE 107 Load and Visualize the Complex 107 Selection Panel 110 Protein Active Site and Rendering 110 Active Site 110 Rendering 112 Ribbon Panel 112 Atoms Panel 113 Contacts Panel 114 Fog and ZClip 115 Molecular Surfaces and Maps 116 2D Ligand Interaction Diagram 119 Rendering and Export Image 120 REFERENCE 120 Subject Index 121 Back Cover 126