CHEMICAL STRUCTURE-BIOLOGICAL ACTIVITY RELATIONSHIPS: QUANTITATIVE APPROACHES

By Q. FAERY

CONTENTS PART 1: INTRODUCTION CHAPTER 1 INTRODUCTION 1 1 OVERVIEW PART 2: MOLECULAR REPRESENTATIONS CHAPTER 2 CHEMISTRY AND GRAPH THEORY 2 1 OVERVIEW 2 2 GRAPH THEORY AND CHEMISTRY 2 3 GRAPH THEORY IN CHEMISTRY 2 4 MATHEMATICAL CHEMISTRY AND CHEMICAL GRAPH THEORY 2 5 SUMMARY REFERENCES CHAPTER 3 STRUCTURE REPRESENTATION 3 1 OVERVIEW 3 2 THE NEED FOR MACHINE-READABLE STRUCTURE REPRESENTATIONS 3 3 ADJACENCY MATRIX 3 4 CONNECTION TABLE 3 5 LINE NOTATIONS 3 5 1 WLN: WISWESSER LINE NOTATION 3 5 2 SMILES: SIMPLIFIED MOLECULAR-INPUT LINE-ENTRY SPECIFICATION 3 5 3 INCHI: IUPAC INTERNATIONAL CHEMICAL IDENTIFIER 3 6 SUMMARY CHAPTER 4 MOLECULAR SIMILARITY 4 1 OVERVIEW 4 2 MOLECULAR SIMILARITY 4 3 SIMILAR PROPERTY PRINCIPLE 4 4 MOLECULAR DESCRIPTORS 4 5 CALCULATION OF MOLECULAR SIMILARITY 4 5 1 SIMILARITY COEFFICIENTS 4 6 MOLECULAR DIVERSITY 4 7 SUMMARY PART 3: MOLECULAR DESCRIPTORS CHAPTER 5 MOLECULAR PROPERTY DESCRIPTORS 5 1 OVERVIEW 5 2 MOLECULAR WEIGHT (MW OR MWT) 5 3 OCTANOL/WATER PARTITION COEFFICIENT (CLOGP) 5 4 TOPOLOGICAL POLAR SURFACE AREA (TPSA) 5 5 HYDROGEN BOND ACCEPTORS AND DONORS (HBA AND HBD) 5 6 LIPINSKI’S RULE-OF-FIVE 5 7 SUMMARY CHAPTER 6 TOPOLOGICAL DESCRIPTORS 6 1 OVERVIEW 6 2 TOPOLOGICAL INDICES 6 2 1 WIENER INDEX 6 2 2 RANDI? INDEX 6 2 3 PETITJEAN INDEX 6 2 4 ZAGREB INDICES 6 3 MOLECULAR FINGERPRINTS 6 3 1 STRUCTURE-KEY FINGERPRINTS 6 3 2 HASH-KEY FINGERPRINTS 6 3 3 LIGAND-BASED TOPOLOGICAL PHARMACOPHORES 6 4 SUMMARY CHAPTER 7 TOPOGRAPHICAL DESCRIPTORS 7 1 OVERVIEW 7 2 TOPOGRAPHIC DESCRIPTORS 7 3 PHARMACOPHORES 7 4 ROCS: RAPID OVERLAY OF CHEMICAL STRUCTURES 7 5 USR: ULTRAFAST SHAPE RECOGNITION 7 6 XED: CRESSET GROUP 7 7 CONFORMER GENERATION AND THE CONFORMER PROBLEM 7 8 SUMMARY PART 4: STATISTICAL LEARNING CHAPTER 8 STATISTICAL LEARNING 8 1 OVERVIEW 8 2 STATISTICAL LEARNING 8 3 UNSUPERVISED LEARNING 8 3 1 OVERVIEW 8 3 2 CLUSTER ANALYSIS 8 3 3 K-MEANS CLUSTERING 8 3 4 STIRLING NUMBERS OF THE SECOND KIND 8 3 5 SELF-ORGANISING MAPS 8 3 6 PRINCIPAL COMPONENT ANALYSIS 8 4 SUPERVISED LEARNING 8 4 1 NAÏVE BAYESIAN CLASSIFICATION 8 4 2 SUPPORT VECTOR MACHINE 8 4 3 PARTIAL LEAST SQUARES 8 5 BEST MODELLING PRACTICE 8 6 SUMMARY PART 5: MODELLING METHODOLOGIES CHAPTER 9 SIMILARITY SEARCHING 9 1 OVERVIEW 9 2 SIMILAR PROPERTY PRINCIPLE 9 3 MOLECULAR SIMILARITY AND VIRTUAL SCREENING 9 4 DATA FUSION 9 5 ENRICHMENT 9 5 1 LIFT PLOTS 9 5 2 CONFUSION MATRIX 9 5 3 RECEIVER OPERATING CHARACTERISTIC CURVES 9 5 4 ENRICHMENT FACTORS 9 6 SUMMARY CHAPTER 10 BIOISOSTERES AND SCAFFOLDS 10 1 OVERVIEW 10 2 A BRIEF HISTORY OF BIOISOSTERISM 10 3 BIOISOSTERIC REPLACEMENT METHODS 10 3 1 KNOWLEDGE-BASED BIOISOSTERIC REPLACEMENTS 10 3 2 INFORMATION-BASED BIOISOSTERIC REPLACEMENTS 10 4 SCAFFOLD REPRESENTATIONS 10 5 SCAFFOLD DIVERSITY ANALYSIS 10 6 SUMMARY CHAPTER 11 CLUSTERING AND DIVERSITY 11 1 OVERVIEW 11 2 DISSIMILARITY-BASED COMPOUND SELECTION 11 3 SPHERE-EXCLUSION 11 4 CELL-BASED DIVERSITY SELECTION 11 5 HIERARCHICAL CLUSTERING 11 6 NON-HIERARCHICAL CLUSTERING 11 7 SUMMARY CHAPTER 12 QUANTITATIVE STRUCTURE–ACTIVITY RELATIONSHIPS 12 1 OVERVIEW 12 2 FREE–WILSON ANALYSIS 12 3 HANSCH–FUJITA ANALYSIS AND TOPLISS TREES 12 4 QSAR MODEL GENERATION 12 5 FEATURE SELECTION 12 6 METHODS FOR ESTIMATING MODEL VALIDITY, PREDICTIVE POWER, AND APPLICABILITY DOMAINS 12 7 AUTOMATED MODEL GENERATION, VALIDATION AND APPLICATION 12 8 SUMMARY CHAPTER 13 PROTEIN–LIGAND DOCKING 13 1 OVERVIEW 13 2 SEARCH ALGORITHMS 13 3 SCORING FUNCTIONS 13 4 GOLD: GENETIC OPTIMISATION FOR LIGAND DOCKING 13 5 MODEL VALIDATION 13 6 DOCKING IN PROSPECTIVE STUDIES 13 7 SUMMARY CHAPTER 14 DE NOVO MOLECULAR DESIGN 14 1 OVERVIEW 14 2 RECEPTOR-BASED METHODS 14 3 FRAGMENT-LINKING METHODS 14 4 FRAGMENT-GROWING METHODS 14 5 SAMPLING CHEMISTRY SPACE 14 6 ATOM-BASED DE NOVO DESIGN 14 7 FRAGMENT-BASED DE NOVO DESIGN 14 8 REACTION-BASED DE NOVO DESIGN 14 9 MULTIOBJECTIVE OPTIMISATION 14 10 SUMMARY PART 6: APPLICATIONS IN MEDICINAL CHEMISTRY CHAPTER 15 APPLICATIONS IN MEDICINAL CHEMISTRY 15 1 OVERVIEW 15 2 EARLY STAGE TARGETS 15 3 HIT GENERATION 15 4 HITS-TO-LEADS 15 5 LEAD OPTIMISATION 15 6 SUMMARY PART 7: SUMMARY AND OUTLOOK CHAPTER 16 SUMMARY AND OUTLOOK 16 1 THE PAST 16 2 THE PRESENT 16 3 THE FUTURE 16 4 SUMMARY