As research progresses and information continues to proliferate in the field of molecular design for therapeutic use, there is a need for a reference that brings current theory and proven practice together in a how-to volume. This reference guides scientists new to the field on how to design small molecules that interact with critical protein targets. The chapters condense useful material into a manageable format which is carefully organized and presented. It offers an essential resource for a variety of chemists in academia, and the biotech and pharmaceutical industries, as well as professionals in complementary fields.
Intro GENE FAMILY TARGETED MOLECULAR DESIGN CONTENTS Preface ACKNOWLEDGMENT Contributors 1 Drug Discoveries by Gene Family 1.1 General Drug Discovery Components 1.2 Further Reading for Expert Knowledge References 2 G-Protein-Coupled Receptors 2.1 Introduction 2.2 GPCR Structure and Function 2.2.1 Subfamilies 2.2.2 Structural Information and Homology Models 2.2.3 Mechanisms of Receptor Modulation 2.2.4 G-Protein Coupling and Assay Formats 2.3 Challenges Facing the Area of GPCR Drug Design 2.3.1 Hit Generation Strategies: Chemogenomics and Privileged Structures 2.3.2 Case History: Calcitonin Gene-Related Peptide Receptor Antagonist (MK-0974, telcagepant) 2.3.3 Case History: Mixed Dopamine/Serotonin Receptor Antagonist As An Atypical Anti-Psychotic 2.3.4 Case History: Chemokine Receptor CCR5 Antagonist Maraviroc (Celsentri™) 2.3.5 Case History: The Discovery of Cinacalcet (Sensipar(®)/Mimpara(®)), a CaSR-Positive Allosteric Modulator 2.4 Conclusions and Outlook References 3 Ion Channels Gene Family: Strategies for Discovering Ion Channel Drugs 3.1 Introduction 3.2 Ion Channel Subfamily Descriptions 3.2.1 Voltage-Gated Ion Channels 3.2.2 Inward Rectifier Potassium Channels 3.2.3 Voltage-Gated Potassium Channels 3.2.4 Calcium-Activated Potassium Channels 3.3 Structure of Potassium Channels 3.4 Criteria for Selection of Targets and Establishing Screens 3.5 A Case Study in Ion Channel Drug Discovery 3.6 Perspective on Ion Channels as Drug Targets References 4 Integrins 4.1 Introduction 4.2 Integrin Inhibitor Discovery 4.2.1 Cyclic Peptides 4.2.2 Peptidomimetic Chemistry 4.2.3 Preferred Peptidomimetic Fragments 4.2.4 I-Domain Integrin Inhibitors 4.2.5 Protein Structure-Based Design 4.3 Challenges-Past and Future. References 5 Strategies for Discovering Kinase Drugs 5.1 Introduction 5.2 Protein Kinase Structural Features 5.3 Generating and Optimizing Kinase Inhibitors 5.3.1 ATP Binding Pocket 5.3.2 Non-ATP Binding Pockets 5.4 Establishing Screens for Understanding Kinase Activity and Selectivity 5.5 Case Studies of Successful Kinase Drug Discovery References 6 Protease-Directed Drug Discovery 6.1 Introduction 6.2 Aspartic Proteases 6.2.1 HIV Protease Inhibitors 6.2.2 Renin 6.3 Metalloproteases 6.3.1 Angiotensin-Converting Enzyme 6.3.2 Matrix Metalloproteases 6.4 Serine Proteases 6.4.1 Dipeptidyl Peptidase 4 (DPP4) 6.4.2 Trypsin-Like S1 Serine Proteases of the Coagulation Cascade 6.5 Cysteine Proteases 6.5.1 Cathepsin K 6.5.2 Caspases 6.6 Perspective on Proteases as Drug Targets References 7 Small-Molecule Inhibitors of Protein-Protein Interactions: Challenges and Prospects 7.1 Introduction 7.2 Structure and Properties of PPI 7.2.1 Constitutive versus Transient PPI 7.2.2 Physicochemical Properties and Residue Propensities of PPI 7.2.3 Binding Energetics and "Hotspots 7.3 Structural and Physicochemical Challenges to Inhibiting PPI with Small Molecules 7.3.1 Key Role of Adaptivity at the Interface 7.3.2 Constraints of "Drug-Like" Chemical Space 7.4 Identifying Hits and Leads Against PPI Targets 7.4.1 Fragment-Based Screening 7.4.2 Validating and Optimizing Hits and Leads 7.5 Assessing the Druggability of New PPI Targets References 8 Transporters 8.1 Introduction 8.2 Methodologies in Transporter Drug Design 8.2.1 Structure-Based Methods 8.2.2 Ligand-Based Methods 8.3 Therapeutic Transporter Targets in Drug Discovery 8.3.1 Vacuolar ATPases 8.3.2 Gastric (P-) ATPases 8.3.3 Neurotransmitter Transporters as Drug Targets. 8.4 Transporters as Liability Targets 8.4.1 P-glycoprotein 8.4.2 OATP1B1 8.5 Application of Methods for Designing Interactions with Liability Targets 8.6 Perspective References 9 Nuclear Receptor Drug Discovery 9.1 Introduction 9.2 Nuclear Receptor Superfamily and Their Functions 9.3 Agonism and Antagonism in Nuclear Receptor Functions 9.3.1 AR Antagonists Effective Toward Mutated Receptors 9.3.2 VDR Agonists and Antagonists 9.3.3 Carboranes as Novel Hydrophobic Pharmacophores 9.4 Medicinal Chemistry of Retinoid Nuclear Receptors 9.4.1 Retinoid and Their Nuclear Receptors 9.4.2 Retinobenzoic Acids 9.4.3 RXR-Selective Ligands 9.5 Clinical Application of Retinoids 9.6 Perspective References 10 Summary and Comparison of Molecules Designed to Modulate Druggable Targets in the Major Gene Families 10.1 Target Class Concept 10.2 Summary of the Unique Features of Each Target Class 10.2.1 GPCR/7TM 10.2.2 Ion Channels 10.2.3 Integrins 10.2.4 Kinases 10.2.5 Proteases 10.2.6 Protein-Protein Interactions 10.2.7 Transporters 10.2.8 Nuclear Receptors 10.3 Perspective References Appendix Index.
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Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, 2021. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries.
Print version: Lackey, Karen Gene Family Targeted Molecular Design