Basic Principles of Drug Discovery and Development

Description

Basic Principles of Drug Discovery and Development presents the multifaceted process of identifying a new drug in the modern era, which requires a multidisciplinary team approach with input from medicinal chemists, biologists, pharmacologists, drug metabolism experts, toxicologists, clinicians, and a host of experts from numerous additional fields. Enabling technologies such as high throughput screening, structure-based drug design, molecular modeling, pharmaceutical profiling, and translational medicine are critical to the successful development of marketable therapeutics. Given the wide range of disciplines and techniques that are required for cutting edge drug discovery and development, a scientist must master their own fields as well as have a fundamental understanding of their collaborator’s fields. This book bridges the knowledge gaps that invariably lead to communication issues in a new scientist’s early career, providing a fundamental understanding of the various techniques and disciplines required for the multifaceted endeavor of drug research and development. It provides students, new industrial scientists, and academics with a basic understanding of the drug discovery and development process. The fully updated text provides an excellent overview of the process and includes chapters on important drug targets by class, in vitro screening methods, medicinal chemistry strategies in drug design, principles of in vivo pharmacokinetics and pharmacodynamics, animal models of disease states, clinical trial basics, and selected business aspects of the drug discovery process. Title-page_2021_Basic-Principles-of-Drug-Discovery-and-Development Basic Principles of Drug Discovery and Development Copyright_2021_Basic-Principles-of-Drug-Discovery-and-Development Copyright Dedication_2021_Basic-Principles-of-Drug-Discovery-and-Development Dedication Contents_2021_Basic-Principles-of-Drug-Discovery-and-Development Contents Foreword_2021_Basic-Principles-of-Drug-Discovery-and-Development Foreword Chapter-1---Drug-discovery-and-development--A_2021_Basic-Principles-of-Drug- 1 Drug discovery and development: An overview of modern methods and principles Drug discovery and development from 20,000Feet (Fig. 1.9) Target selection: the first step forward Hit identification: finding a starting point Identify a clinical candidate: juggling the properties Questions References Chapter-2---The-drug-discovery-process--Fro_2021_Basic-Principles-of-Drug-Di 2 The drug discovery process: From ancient times to the present day The age of botanicals: pre-industrial drug discovery Early biotherapeutics: before the biotechnology revolution Paul Ehrlich: the father of modern drug discovery Milestones in drug discovery Milestones in animal models: breeding a better model The Wistar rat Immunocompromised mice The nude mouse34 The SCID mouse Transgenic animal models Knockout animal models Milestones in molecular science X-ray crystallography Molecular modeling and computational chemistry High-throughput technology: chemical synthesis and screening science Milestones in biotechnology Recombinant DNA and transfection technology Polymerase chain reaction technology DNA Sequencing and genomics Proteomics Monoclonal antibody and hybridoma technology The rise of biologics and macromolecular therapeutics Societal and governmental impacts The Pure Food and Drug Act of 1906180 The Elixir of Sulfanilamide Disaster of 1937184 The Thalidomide story186 Regulatory milestones Durham-Humphrey Amendment of 1951187 Kefauver-Harris Amendment of 1962188 Hatch-Waxman Act of 1984189 Biologics Price Competition and Innovation Act of 2009190 Future developments in drug discovery Questions References Chapter-3---Classical-targets-in-d_2021_Basic-Principles-of-Drug-Discovery-a 3 Classical targets in drug discovery Protein structure Enzymes Inhibition of enzymes G-protein-coupled receptors G-protein-dependent signaling pathways Cyclic adenosine monophosphate signaling IP3 signaling β-Arrestin pathways G-protein-coupled receptor signaling pathways Modulating G-protein-coupled receptor signaling Ion channels Gating mechanisms Ligand-gated channels Voltage-gated channels Other gating mechanisms Membrane transport proteins (transporters) Nuclear receptors Nuclear receptor signaling pathways Modulating nuclear receptor activity Biomolecular interactions: protein/protein, protein/DNA, and protein/RNA interfaces Types of “hot spots” in biomolecular interactions Stabilizing biomolecular interactions Questions References Chapter-4---In-vitro-screening-_2021_Basic-Principles-of-Drug-Discovery-and- 4 In vitro screening systems The language of screening: basic terms Concentration–response curves and IC50s Dissociation constants (Kd) and inhibition constants (Ki) Efficacy versus binding: EC50s Agonist, partial agonist, antagonist, allosteric modulators, and inverse agonists Agonists and partial agonists Antagonists Basal activity and inverse agonist Receptor reserve Allosteric modulation Streptavidin and biotin Biochemical versus cellular assays Assay systems and methods of detection Radioligand systems Scintillation proximity assay Enzyme-linked immunosorbent assay Fluorescence-based assay systems Fluorescence polarization Fluorescence resonance energy transfer Time-resolved fluorescence resonance energy transfer Amplified luminescent proximity homogeneous assay (AlphaScreen™) Fluorescent detection of calcium flux Reporter gene assays Chloramphenicol acetyltransferase β-Lactamase reporter assays Luciferase reporter assays Bioluminescence resonance energy transfer assays Kinetic fluorescent measurement systems Label-free assay systems Cellular dielectric spectroscopy Optical biosensors Surface plasmon resonance technology Electrophysiological patch clamp Thermal shift assay High content screening General consideration for all screening methods Questions References Chapter-5---Medicinal-chemi_2021_Basic-Principles-of-Drug-Discovery-and-Deve 5 Medicinal chemistry Structure–activity relationships and structure–property relationships The role of chirality Push and pull in structure–activity relationships Quantitative structure–activity relationships The pharmacophore Developing an structure–activity relationship data set The structure–activity relationship cycle Bioisosterism Structure–activity relationship, selectivity, and physicochemical properties “Drug-like” guidelines Questions References Chapter-6---In-vitro-ADME-and-in-vivo_2021_Basic-Principles-of-Drug-Discover 6 In vitro ADME and in vivo pharmacokinetics Absorption Solubility Permeability Distribution Permeability Transporters Plasma protein binding Elimination pathways Metabolism Excretion In vitro ADME model systems In Vivo pharmacokinetics Volume of distribution Clearance Half-life Bioavailability Species selection Questions References Chapter-7---Animal-models-of-dise_2021_Basic-Principles-of-Drug-Discovery-an 7 Animal models of disease states Sources of animal models Validity of animal models Species selection Number of animals Exemplary animal models by disease category Animal models in neuroscience The forced swimming test: A model of depression19 The elevated plus maze: A measure of anxiety20 The novel object recognition test: A model of memory and cognition21 Contextual fear conditioning model: A model of contextual learning22 The Morris water maze: A model of spatial learning and memory23 Animal models of neurodegeneration The SOD1G93A mouse of amyotrophic lateral sclerosis (ALS)24 The MPTP model of Parkinson’s disease25 Animal models of cardiovascular disease Models of hypertension Models of hyperlipidemia and high cholesterol Models of atrial fibrillation Models of heart failure Animal models of infectious disease Murine thigh infection model Murine model of systemic infection Mouse model of influenza virus infection Limitations of animal models of infection Animal models of oncology Mouse xenograft tumor model Mouse allograft tumor model Genetically engineered mouse models of cancer Animal models of pain The Von Frey test The Ramdall-Selitto test Heat based models Inflammation based models Surgical models General consideration for pain models Animal models of diabetes Animal models of drug addiction Conclusion Questions References Chapter-8---Safety-and-toxic_2021_Basic-Principles-of-Drug-Discovery-and-Dev 8 Safety and toxicology Sources of toxicity Acute versus chronic toxicity Cytotoxicity Carcinogenicity, genotoxicity, and mutagenicity Drug–drug interactions Cardiovascular safety and toxicology studies Central nervous system safety and toxicology studies Immune system-mediated safety issues Teratogenicity In vivo toxicity and safety studies Questions References Chapter-9---Antibody-drug-dis_2021_Basic-Principles-of-Drug-Discovery-and-De 9 Antibody-drug discovery IgG structure and function Antibody therapy drug discovery Hybridoma technology Antibody phage display Modified monoclonal antibodies General considerations Conclusion Questions References Chapter-10---Basics-of-clinical_2021_Basic-Principles-of-Drug-Discovery-and- 10 Basics of clinical trials Before the clinic Drug supply Delivery methods Formulation Investigational new drug application Phase 1 clinical trials Phase 2 clinical trials Phase 3 clinical trials Phase 4 clinical trials Adaptive clinical trial design59 Meta-analysis of clinical trial data Questions References Chapter-11---Translational-medicine_2021_Basic-Principles-of-Drug-Discovery- 11 Translational medicine and biomarkers Definition of a biomarker and their classification Characteristics and impact of biomarkers Biomarkers versus surrogate endpoints Imaging technologies The practical application of biomarkers Dipeptidyl peptidase IV inhibitors (Januvia) Physiological measurements as biomarkers: Orexin antagonists FDG PET imaging agent The neurokinin 1 receptor, depression, and PET imaging: The Aprepitant story Cancer biomarkers Conclusion Questions References Chapter-12---Organizational-consideration-an_2021_Basic-Principles-of-Drug-D 12 Organizational consideration and trends in the pharmaceutical industry Organizational structures of pharmaceutical companies Business divisions interactions The discovery project team evolutionary cycle The business climate Mergers and acquisitions Contract research organizations Academic drug discovery Funding issues Conclusion Questions Appendix 1 References Chapter-13---Intellectual-property-and-p_2021_Basic-Principles-of-Drug-Disco 13 Intellectual property and patents in drug discovery Patentable subject matter Inherent properties and patentability Novelty and the prior art Obviousness and the prior art Inventorship Assignment and ownership Classification of patents and patent applications Impact of overlapping patents Patent applications and their contents Contents of a patent application Conclusion Questions References Chapter-14---Case-studies-in-drug_2021_Basic-Principles-of-Drug-Discovery-an 14 Case studies in drug discovery Tamiflu: From mechanism of action to marketed drug Histone deacylase inhibitors: Physicochemical optimization via structural change HIV protease inhibitors: Chemically complex miracle drugs Nitrofurantoin: A surprisingly successful drug Seldane® (Terfenadine) vs Allegra® (Fexofenadine): Metabolism matters: Safety Claritin® (Loratadine) versus Clarinex® (Desloratadine): Metabolism matters: Pharmacokinetics MPTP: Parkinson’s disease in a bottle Bupropion and Methylphenidate: Improving performance via formulation changes Selective inhibition of COX-2: The impact of an inadequate written description Antibiotic resistant bacteria and the development of β-lactamase inhibitors Association for Molecular Pathology vs Myriad Genetics: The validity of gene patents Conclusion Questions References Answers-to-questions-in-textbook-_2021_Basic-Principles-of-Drug-Discovery-an Answers to questions in textbook by chapter Chapter 1 Chapter 2 Chapter 3 Chapter 4 Chapter 5 Chapter 6 Chapter 7 Chapter 8 Chapter 9 Chapter 10 Chapter 11 Chapter 12 Chapter 13 Chapter 14 Subject-Index_2021_Basic-Principles-of-Drug-Discovery-and-Development Subject Index Drug-Index_2021_Basic-Principles-of-Drug-Discovery-and-Development Drug Index