Note: Exploiting Chemical Diversity For Drug Discovery -- Contents -- Section 1 Operational Developments in Chemistry -- Chapter 1 The Use of Polymer-Assisted Solution-Phase Synthesis and Automation for the High-Throughput Preparation of Biologically Active Compounds -- 1 Introduction -- 2 PASP Synthesis Approaches to Biologically Active Compounds -- 2.1 Applications to the Synthesis of Commercial Drug Molecules -- 2.2 Applications of PASP to the Synthesis of Biologically Active Natural Products -- 2.3 PASP Synthesis in the Library Production of Biologically Active Small Molecules -- 3 Automated PASP Synthesis of Biologically Active Molecules -- 3.1 Stepwise Automation of PASP Synthesis in Batch Mode -- 3.2 Fully Automated PASP Synthesis of Drug-Like Molecules in Batch Mode -- 3.3 Flow Chemistry and Automation in the Synthesis of Drug-Like Molecules -- 4 Conclusion -- References -- Chapter 2 Accelerated Chemistry: Microwave, Sonochemical, and Fluorous Phase Techniques -- 1 Introduction -- 2 Microwave Enhanced Chemistry -- 2.1 General -- 2.2 Applications in Medicinal Chemistry -- 2.3 Applications in Solid-Phase Chemistry -- 3 Sonochemistry as a Means to Accelerate Synthesis -- 3.1 General -- 3.2 Organometallic Sonochemistry -- 3.3 Heterocyclic and Pericyclic Chemistry -- 3.4 Applications in Medicinal Chemistry -- 4 Fluorous Phase Techniques -- 4.1 General -- 4.2 Reagents, Linkers, and Scavengers -- 4.3 Fluorous Protecting Groups -- 4.4 Fluorous Mixture Synthesis -- 4.5 Peptides and Oligosaccharides -- 4.6 Fluorous Applications in High-Throughput Chemistry -- 4.7 Microwave-Enhanced Fluorous Chemistry -- 5 Conclusion -- Acknowledgements -- References -- Section 2 Conceptual Advances in Synthesis: "Prospecting" - Design of Discovery Libraries and the Search for Hits -- Chapter 3 Biosynthesis of "Unnatural" Natural Products -- 1 Introduction. , 1.1 Polyketide Assembly -- 1.2 Three Major Classes of Polyketide Synthases -- 1.3 Methods for Engineered Biosynthesis -- 2 Type I Polyketide Synthases -- 2.1 Modular Architecture -- 2.2 The Erythromycin Synthase -- 2.3 Engineered Biosynthesis of Multimodular PKS Products -- 2.3.1 Domain Engineering -- 2.3.2 Module Engineering -- 2.3.3 Primer Unit Engineering and Precursor-Directed Biosynthesis -- 2.4 Multimodular PKSs that Exhibit Special Features -- 2.5 Fungal Type I PKSs -- 3 Type II Polyketide Synthases -- 3.1 Dissociated Architecture -- 3.2 Combinatorial Biosynthesis of Type II Polyketides -- 3.2.1 Chain-Length Variations -- 3.2.2 Mix and Match of Tailoring Enzymes -- 3.2.3 Primer Unit Modifications -- 3.2.4 Reshuffling of DownstreamTailoring Enzymes -- 4 Type III Polyketide Synthase -- 4.1 Type III PKS Consists of a Homodimeric Ketosynthase -- 4.2 Engineered Biosynthesis of Type III Polyketides -- 5 Conclusions -- Acknowledgments -- References -- Chapter 4 Combinatorial Synthetic Design: The Balance of Novelty and Familiarity -- 1 Biological Macromolecules - Strength in Numbers -- 1.1 Congruence between Biological and Chemical Space -- 1.2 The Libraries are Exhaustive within the Defined Boundaries -- 1.3 Highly Optimized Synthesis Procedures were Available -- 2 Oligomer Synthesis - Improving on Mother Nature -- 3 Random, Discovery, or Prospecting Libraries - the Quest for the Universal Scaffold -- 4 Privileged Scaffolds - Look Where the Light is Brightest -- 5 The Decoration or Synthesis of Novel Scaffolds - Aid for the Underprivileged -- 6 Target Class Libraries - Diversity with a Purpose -- 7 Peptide and Nucleotide Libraries Redux -- 8 Lead Discovery or Drug Discovery - Size does Matter -- 9 Natural Product Scaffolds for Combinatorial Chemistry - Why Reinvent the Wheel?. , 10 From Natural Products to Natural Product-Like Libraries - Hubris or Progress? -- 11 Lead Discovery and Combinatorial Chemistry - What have We Learned? -- 11.1 The Drug-Discovery Process cannot be Simplified to a Single Blueprint -- 11.2 Combinatorial Chemistry is an Extremely Powerful Technology -- 11.3 Combinatorial Chemistry is at its Best in Lead Optimization -- 11.4 Combinatorial Chemistry is about Making the Compounds that Fit Your Needs, not How They are Made -- References -- Chapter 5 Compound Collections: Acquisition, Annotation, and Access -- 1 Introduction -- 2 Commercial Offerings -- 3 Companies Providing Non-Proprietary, Non-Parallel Synthesised Libraries (Shared-Pool/'Collected Collections') -- 4 Companies Providing In-House Designed, Parallel Synthesised Libraries -- 5 Compound Selection and Database Filtering -- 6 Sub-structure Similarity/Dissimilarity -- 7 Pharmacophore Analysis -- 8 Annotation -- 9 Lipinski Rule-of-Five (LRoF) -- 10 Topological Polar Surface Area (tPSA) and Blood-Brain-Barrier Permeability (Log BB) -- 11 Solubility -- 12 Examples of the Use of Chemical Annotation and Pharmacophore-Based Lead-Hopping -- 13 Compound Acquisition -- Acknowledgments -- References -- Chapter 6 Chemical Diversity: Definition and Quantification -- 1 Introduction -- 2 Diversity Metrics -- 2.1 Distance-Based Metrics -- 2.2 Cell-Base Diversity Metrics -- 2.3 Variance-Based Diversity Metrics -- 3 Molecular Description -- 3.1 Two-Dimensional Descriptors -- 3.2 Three-Dimensional Descriptors -- 3.3 Physicochemical and Electronic Descriptors -- 3.4 Descriptor Selection -- 4 Dimensionality Reduction -- 4.1 Principle Component Analysis -- 4.2 Singular-Value Decomposition -- 4.3 Factor Analysis (FA) -- 4.4 MultiDimensional Scaling -- 4.5 Stochastic Proximity Embedding -- 5 Subset Selection and Classification -- 5.1 Clustering. , 5.2 Partitioning Methods -- 5.3 Experimental Design -- 5.4 Reagent-Based Versus Product-Based Design -- 5.5 Random Versus Rational Design -- 6 Conclusion -- Abbreviations -- References -- Section 3 Conceptual Advances in Synthesis: "Mining" - Turning a Hit into a Lead -- Chapter 7 Focused Libraries: The Evolution in Strategy from Large-Diversity Libraries to the Focused Library Approach -- 1 Introduction -- 2 A Synergistic, Multidisciplinary Approach to Library Conception -- 2.1 Improvements in Synthetic Methods -- 2.2 Impact of In Silico Tools for Library Design -- 2.3 Influence of Biology in Library Design -- 3 Library Design Concepts -- 3.1 Impact of Diversity on Library Design -- 3.2 Diversity-Oriented Synthesis in Prospecting Library Design -- 3.3 Target-Oriented Library Design -- 3.4 Focus on Drug-Like Libraries -- 4 Focused Libraries -- 4.1 Libraries Focused on Pharmacophore Models -- 4.2 Libraries Focused on Privileged Structures -- 4.3 Libraries Focused on Target Classes -- 4.3.1 GPCR-Targeted Libraries -- 4.3.2 Kinase-Targeted Libraries -- 4.3.3 Natural Product-Based Focused Libraries -- 4.4 Early Optimization or Hit-to-Lead Libraries -- 5 Summary -- References -- Chapter 8 Translating Peptides into Small Molecules -- 1 Peptides as Drugs: The Good, the Bad and the Ugly -- 2 Origin of Biologically Active Peptides -- 3 General Strategy for Translating Peptides into Small Molecules -- 4 Tailoring Peptide Sequences for their Translation into Small Molecules -- 5 Transformation of Peptide Ligands into Small Molecules using Computational Approaches -- 6 Conclusion -- References -- Section 4 Operational Developments in Screening and High Throughput Assays -- Chapter 9 High-Density Plates, Microarrays, Microfluidics -- 1 Functional High-Density Well Plates for High-Throughput Assays -- 1.1 Sample Plates for Low-Volume High-Throughput Screening. , 1.2 High-Density Assay Plates for HTS and Multidimensional Compound Profiling -- 1.3 Technical, Biological, and Economical Limits for Assay Miniaturization in High-Density Plates -- 1.4 384-Microtube Plate for High-Throughput Retrieval of Compound Subsets -- 1.5 Sample Management for HTS and Multidimensional Compound Profiling -- 2 Parallel Liquid Handling of Low-Volume Samples -- 2.1 Pipetting and Dispensing in High-Density Plates -- 2.2 High-Throughput Aliquoting of the HTS Library -- 2.3 A Microfluidic Well Plate for High-Throughput Solid/Liquid Separations -- 3 Microarray Assays on Chips -- 3.1 Microchannel Assay: A New Generation of Miniaturized Multiplexed Bioassays -- 4 Prospects for Multiparameter Assays -- Acknowledgment -- References -- Chapter 10 Fluorescence Technologies for the Investigation of Chemical Libraries -- 1 Introduction -- 2 Dissociation-Enhanced Lanthanide Fluoroimmunoassay -- 3 Enzyme Fragment Complementation -- 4 Fluorescence Polarization -- 5 Fluorescence Correlation Spectroscopy -- 6 Amplified Luminescent Proximity Homogeneous Assay (AlphaScreen™) -- 7 Fluorescence Resonance Energy Transfer -- 8 Bioluminescence Resonance Energy Transfer -- 9 Homogeneous Time Resolved Fluorescence -- 10 Conclusion -- References -- Chapter 11 The Use of Genetically Engineered Cell-Based Assays in in-vitro Drug Discovery -- 1 Introduction -- 2 Genetic Engineering for Cell-Based Assays -- 2.1 Expression Systems -- 2.2 Choice of Cell Line and Promoter -- 2.3 Chromosomal Integration Site -- 3 Reporter-Based Assays -- 3.1 Chloramphenicol Acetyl Transferase, Secreted Placental Alkaline Phosphatase, β-Galactosidase -- 3.2 Green Fluorescent Protein -- 3.3 Luciferase -- 3.4 β-Lactamase -- 3.5 Examples of Applications -- 4 Assays to Measure Intracellular Calcium -- 5 Assays to Monitor Protein-Protein Interactions. , 5.1 Bioluminescence Resonance Energy Transfer and Fluorescence Resonance Energy Transfer.

Note: Intro -- Title Page -- Copyright Page -- Contents -- Contributors -- Introduction -- References -- CHAPTER 1 ATTRITION IN DRUG DISCOVERY AND DEVELOPMENT -- 1.1 "The Graph" -- 1.2 The Sources of Attrition -- 1.3 Phase II Attrition -- 1.3.1 Target Engagement -- 1.3.2 Clinical Trial Design -- 1.4 Phase III Attrition -- 1.4.1 Safety Attrition in Phase III -- 1.5 Regulation and Attrition -- 1.6 Attrition in Phase IV -- 1.7 First in Class, Best in Class, and the Role of the Payer -- 1.8 Portfolio Attrition -- 1.9 "Avoiding" Attrition -- 1.9.1 Drug Combinations and New Formulations -- 1.9.2 Biologics versus Small Molecules -- 1.9.3 Small-Molecule Compound Quality -- 1.10 Good Attrition versus Bad Attrition -- 1.11 Summary -- References -- CHAPTER 2 COMPOUND ATTRITION AT THE PRECLINICAL PHASE -- 2.1 Introduction: Attrition in Drug Discovery and Development -- 2.2 Target Identification, hts, and Lead Optimization -- 2.3 Resurgence of Covalent Inhibitors -- 2.4 In Silico Models to Enhance Lead Optimization -- 2.5 Structure-Based and Property-Based Compound Design in Lead Optimization -- 2.5.1 Risks Associated with Operating in Nondrug-Like Space -- 2.6 Attrition Due to Adme Reasons -- 2.6.1 Metabolism, Bioactivation, and Attrition -- 2.6.2 PK/PD Modeling in Drug Discovery to Reduce Attrition -- 2.6.3 Human PK Prediction Uncertainties -- 2.7 Attrition Due to Toxicity Reasons -- 2.8 Corporate Culture and Nonscientific Reasons for Attrition -- 2.9 Summary -- References -- CHAPTER 3 ATTRITION IN PHASE I -- 3.1 Introduction -- 3.2 Attrition in Phase I Studies and Paucity of Published Information -- 3.3 Drug Attrition in not fih Phase I Studies -- 3.4 Attrition in fih Studies due to pk -- 3.4.1 Attrition due to Pharmacogenetic Factors -- 3.5 Attenuation of pk Failure -- 3.5.1 Preclinical Methods (In Vivo) -- 3.5.2 Preclinical Methods (In Vitro). , 3.5.3 Phase 0, Microdose Studies in Humans -- 3.5.4 Responding to Unfavorable PK Characteristics -- 3.6 Phase I Oncology Studies -- 3.7 Toleration and Attrition in Phase I Studies -- 3.7.1 Improving the Hepatic Toleration of Compounds -- 3.7.2 Rare Severe Toxicity in Phase I Studies -- 3.8 Target Occupancy and go/no-go Decisions to Phase II Start -- 3.9 Conclusions -- References -- CHAPTER 4 COMPOUND ATTRITION IN PHASE II/III -- 4.1 Introduction -- 4.2 Attrition Rates: How Have they Changed? -- 4.3 Why do Drugs Fail in Phase II/III? Lack of Efficacy or Marginal Efficacy Leading to Likely Commercial Failure -- 4.4 Toxicity -- 4.5 Organizational Culture -- 4.6 Case Studies for Phase II/III Attrition -- 4.6.1 Torcetrapib -- 4.6.2 Dalcetrapib -- 4.6.3 Onartuzumab -- 4.6.4 Bapineuzumab -- 4.6.5 Gantenerumab -- 4.6.6 Solanezumab -- 4.6.7 Pomaglumetad Methionil (LY-2140023) -- 4.6.8 Dimebon (Latrepirdine) -- 4.6.9 BMS-986094 -- 4.6.10 TC-5214 (S-Mecamylamine) -- 4.6.11 Olaparib -- 4.6.12 Tenidap -- 4.6.13 NNC0109-0012 (RA) -- 4.6.14 Omapatrilat -- 4.6.15 Ximelagatran -- 4.7 Summary and Conclusions -- References -- CHAPTER 5 POSTMARKETING ATTRITION -- 5.1 Introduction -- 5.2 On-Target Pharmacology-Flawed Mechanism -- 5.2.1 Alosetron -- 5.2.2 Cerivastatin -- 5.2.3 Tegaserod -- 5.3 Off-Target Pharmacology, Known Receptor: An Issue of Selectivity -- 5.3.1 Fenfluramine and Dexfenfluramine -- 5.3.2 Rapacuronium -- 5.3.3 Astemizole, Cisapride, Grepafloxacin, and Thioridazine -- 5.4 Off-Target Pharmacology, Unknown Receptor: Idiosyncratic Toxicology -- 5.4.1 Benoxaprofen -- 5.4.2 Bromfenac -- 5.4.3 Nomifensine -- 5.4.4 Pemoline -- 5.4.5 Remoxipride -- 5.4.6 Temafloxacin -- 5.4.7 Tienilic acid -- 5.4.8 Troglitazone -- 5.4.9 Tolcapone -- 5.4.10 Trovafloxacin -- 5.4.11 Valdecoxib -- 5.4.12 Zomepirac -- 5.5 Conclusions -- References. , CHAPTER 6 INFLUENCE OF THE REGULATORY ENVIRONMENT ON ATTRITION -- 6.1 Introduction -- 6.1.1 How the Regulatory Environment has Changed Over the Last Two Decades -- 6.1.2 Past and Current Regulatory Attitude to Risk Analysis and Risk Management -- 6.2 Discussion -- 6.2.1 What Stops Market Approval? -- 6.2.2 Impact of Black Box Warnings -- 6.2.3 Importance and Impact of Pharmacovigilance -- 6.2.4 Prospects of Market Withdrawals for New Drugs -- 6.2.5 What Are the Challenges for the Industry Given the Current Regulatory Environment? -- 6.2.6 Future Challenges for Both Regulators and the Pharmaceutical Industry -- 6.3 Conclusion -- References -- CHAPTER 7 EXPERIMENTAL SCREENING STRATEGIES TO REDUCE ATTRITION RISK -- 7.1 Introduction -- 7.2 Screening Strategies in hit Identification -- 7.2.1 Screening Strategies and Biology Space -- 7.2.2 Screening Strategies and Chemical Space -- 7.2.3 High-Throughput Screening Technologies -- 7.2.4 Future Directions for High-Throughput Screening -- 7.3 Screening Strategies in hit Validation and Lead Optimization -- 7.4 Screening Strategies for Optimizing pk and Safety -- 7.4.1 High-Throughput Optimization of PK/ADME Profiles -- 7.4.2 Early Safety Profiling -- 7.4.3 Future Directions for ADME and Safety in Lead Optimization -- 7.5 Summary -- References -- CHAPTER 8 MEDICINAL CHEMISTRY STRATEGIES TO PREVENT COMPOUND ATTRITION -- 8.1 Introduction -- 8.2 Picking the Right Target -- 8.3 Finding Starting Compounds -- 8.4 Compound Optimization -- 8.4.1 Drug-Like Compounds -- 8.4.2 Structure-Based Drug Design -- 8.4.3 The Thermodynamics and Kinetics of Compound Optimization -- 8.4.4 PK -- 8.4.5 Toxicity -- 8.5 Summary -- References -- CHAPTER 9 INFLUENCE OF PHENOTYPIC AND TARGET‐BASED SCREENING STRATEGIES ON COMPOUND ATTRITION AND PROJECT CHOICE -- 9.1 Drug Discovery Approaches: A Historical Perspective. , 9.1.1 Phenotypic Screening -- 9.1.2 Target-Based Screening -- 9.1.3 Recent Changes in Drug Discovery Approaches -- 9.2 Current Phenotypic Screens -- 9.2.1 Definition of Phenotypic Screening -- 9.2.2 Recent Anti-infective Projects -- 9.2.3 Recent CNS Projects -- 9.3 Current Targeted Screening -- 9.3.1 Definition of Targeted Screening -- 9.3.2 Recent Anti-infective Projects -- 9.3.3 Recent CNS Projects -- 9.4 Potential Attrition Factors -- 9.4.1 Technical Doability and Hit Identification -- 9.4.2 Compound SAR and Properties -- 9.4.3 Safety -- 9.4.4 Translation to the Clinic -- 9.5 Summary and Future Directions -- 9.5.1 Summary of Impact of Current Approaches -- 9.5.2 Future Directions -- 9.5.3 Conclusion -- References -- CHAPTER 10 IN SILICO APPROACHES TO ADDRESS COMPOUND ATTRITION -- 10.1 In Silico Models help to Slleviate the Process of Finding both Safe and Efficacious Drugs -- 10.2 Use of in Silico Approaches to Reduce Attrition Risk at the Discovery Stage -- 10.3 Ligand-Based and Structure-Based Models -- 10.4 Data Quality -- 10.5 Predicting Model Errors -- 10.6 Molecular Properties and Their Impact on Attrition -- 10.7 Modeling of Adme Properties and their Impact of Reducing Attrition in the Last Two Decades -- 10.8 Approaches to Modeling of Tox -- 10.9 Modeling pk and pd and Dose Prediction -- 10.10 Novel in Silico Approaches to Reduce Attrition Risk -- 10.11 Conclusion -- References -- CHAPTER 11 CURRENT AND FUTURE STRATEGIES FOR IMPROVING DRUG DISCOVERY EFFICIENCY -- 11.1 General Introduction -- 11.2 Scope -- 11.3 Neglected Diseases -- 11.3.1 Introduction -- 11.3.2 Control of NTDs -- 11.3.3 Drug Discovery Potential of Neglected Diseases -- 11.4 Precompetitive Drug Discovery -- 11.4.1 Introduction -- 11.4.2 Virtual Discovery Organizations -- 11.4.3 Collaborations with Academic Laboratories -- 11.4.4 CoE and Incubators. , 11.4.5 Screening Data and Compound File Sharing -- 11.5 Exploitation of Genomics -- 11.5.1 Introduction -- 11.5.2 Target Identification and Validation -- 11.5.3 Target-Based Drug Discovery -- 11.5.4 Phenotypic Whole-Cell Screening -- 11.5.5 Individualized Therapy and Therapies for Special Patient Populations -- 11.6 Outsourcing Strategies -- 11.6.1 Introduction -- 11.6.2 Research Contracting in Drug Discovery -- 11.7 Multitarget Drug Design and Discovery -- 11.7.1 Introduction -- 11.7.2 Rationale for Multitargeted Drugs -- 11.7.3 Designed Multitarget Compounds for Neglected Diseases -- 11.8 Drug Repositioning and Repurposing -- 11.8.1 Introduction -- 11.8.2 Cell Biology Approach -- 11.8.3 Exploitation of Genome Information -- 11.8.4 Compound Screening Studies -- 11.8.5 Exploitation of Coinfection Drug Efficacy -- 11.8.6 In Silico Computational Technologies -- 11.9 Future Outlook -- References -- CHAPTER 12 IMPACT OF INVESTMENT STRATEGIES, ORGANIZATIONAL STRUCTURE AND CORPORATE ENVIRONMENT ON ATTRITION, AND FUTURE INVESTMENT STRATEGIES TO REDUCE ATTRITION -- 12.1 Attrition -- 12.2 Costs -- 12.2.1 The Costs of Creating a New Medicine -- 12.2.2 The Costs of Not Creating a New Medicine -- 12.3 Investment Strategies -- 12.3.1 RoI -- 12.3.2 Investment in a Portfolio of R& -- D Projects -- 12.3.3 Asset-Centered Investment -- 12.3.4 Sources of Funds -- 12.4 Business Models -- 12.4.1 Fipco -- 12.4.2 Fully Integrated Pharmaceutical Network (FIPNET) -- 12.4.3 Venture-Funded Biotech -- 12.4.4 Fee-for-Service CRO -- 12.4.5 Hybrids -- 12.4.6 Academic Institute -- 12.4.7 Social Enterprise -- 12.5 Portfolio Management -- 12.5.1 Portfolio Construction -- 12.5.2 Project Progression -- 12.5.3 The Risk Transition Point -- 12.6 People -- 12.6.1 Motivation -- 12.6.2 Culture and Leadership -- 12.6.3 Sustainability -- 12.7 Future -- 12.7.1 Business Structures. , 12.7.2 Skilled Practitioners.

Note: Cover -- Title -- Copyright -- Dedication -- Contents -- List of Illustrations -- Acknowledgments -- List of Abbreviations and Acronyms -- CHAPTER 1 Introduction -- CHAPTER 2 Equilibrium and Other Core Assumptions -- CHAPTER 3 Modeling with Hard Constraints -- CHAPTER 4 Modeling with Soft Constraints -- CHAPTER 5 The Treatment of Change -- CHAPTER 6 The Characterization of Consumption -- CHAPTER 7 Summary -- Notes -- References -- Index -- Author Index.

Note: Cover -- Title -- Copyright -- Dedication -- Contents -- List of Figures -- Foreword -- Acknowledgments -- 1 Introduction -- 2 The Modeling Framework -- 2.1 Nomenclature -- 2.2 Basic Modeling of Consumption -- 2.3 Basic Model of Physical/Production -- 2.4 Other Aspects of Modeling -- 3 The Framework and Development of Peak Load Pricing -- 3.1 Basic Peak Load Pricing Theory -- 3.2 Early Days of Tariff Evolution -- 3.3 Postwar Theory and Application of Capacity Charging-The Drèze Approach -- 3.4 Elastic Demand for Capacity- The Steiner Framework -- 3.5 Efficiency of Rationing of Demand -- 3.6 Pricing under Stochastic Demand- The Brown and Johnson Framework -- 3.7 Modeling under Variable Rationing Efficiency-The Visscher Framework -- 3.8 Demand for Capacity with Stochastic Elastic Demand-the Carlton Framework -- 3.9 Optimal Pricing, Capacity and the Technology Frontier-Crew and Kleindorfer -- 3.10 Further Development of the Price Vector-from Dansby -- 3.11 Stochastic Variation in both Production and Demand-the Chao Framework -- 3.12 Discussion of the Pricing Analyses -- 4 Relaxing the Hard Capacity Constraint -- 4.1 Introduction -- 4.2 The Hirshleifer Framework -- 4.3 Optimizing with Decreasing Returns to Scale-The Panzar Framework -- 4.4 Concluding Discussion of Soft Constraints -- 5 Modeling Capacity Using Derivatives -- 5.1 Power Markets -- 5.2 Single Period-Modeling Using Options of "European" Type -- 5.3 Modeling System Operator Option Procurement in the One-Period Setting -- 5.4 Modeling More Complex Options in the One-Period Setting -- 5.5 Many Periods-Modeling Using Options of "American" Type -- 5.6 Modeling System Operator Option Procurement in the Unrestricted Many-Period Setting -- 5.7 Modeling Many Periods under Constraint Using Options of "Swing" Type. , 5.8 Modeling System Operator Option Procurement in the Restricted Many-Period Setting -- 5.9 Modeling Real Assets -- 5.10 Modeling Prices and Price Dynamics -- 6 Capacity Mechanisms -- 6.1 Types of Capacity Mechanism -- 6.2 Development of the Key Variables in the ICAP Model -- 6.3 Development of ICAP toward the Use of Strike Prices -- 6.4 Division of the Market to Regimes -- 6.5 General Development of Capacity Mechanisms toward Energy-Only Markets -- 7 The Power Complex -- 7.1 The Demand Side -- 7.2 Transmission and Interconnection -- 7.3 Peak Load Pricing in Distribution Charging -- 7.4 Commercial Arrangements on Lost Load -- 8 Final Comments -- Notes -- References -- Index.

Note: Includes bibliographies and index. The basic structure of clouds of diffusing contaminant / by P.C. Chatwin and P.J. Sullivan -- Concentration fluctuations iatmospheric diffusion / by J.R. Thomas -- Continuous plumes, their iatmospheric diffusion / by J.R. Thomas -- Continuous plumes, their

Note: Description based on print version record , Master and use copy. Digital master created according to Benchmark for Faithful Digital Reproductions of Monographs and Serials, Version 1. Digital Library Federation, December 2002.