Chemokines: Chemokines and Their Receptors in Drug Discovery (Topics in Medicinal Chemistry Book 14)

Medicinal chemistry is both science and art. The science of medicinal chemistry offers mankind one of its best hopes for improving the quality of life. The art of medicinal chemistry continues to challenge its practitioners with the need for both intuition and experience to discover new drugs. Hence sharing the experience of drug research is uniquely beneficial to the field of medicinal chemistry. Drug research requires interdisciplinary team-work at the interface between chemistry, biology and medicine. Therefore, the topic-related series Topics in Medicinal Chemistry covers all relevant aspects of drug research, e.g. pathobiochemistry of diseases, identification and validation of (emerging) drug targets, structural biology, drugability of targets, drug design approaches, chemogenomics, synthetic chemistry including combinatorial methods, bioorganic chemistry, natural compounds, high-throughput screening, pharmacological in vitro and in vivo investigations, drug-receptor interactions on the molecular level, structure-activity relationships, drug absorption, distribution, metabolism, elimination, toxicology and pharmacogenomics. In general, special volumes are edited by well known guest editors. 3.2 CCR5 Interaction with Maraviroc and Structural Basis for Allostery3.3 Before the CXCR4 Structure: Computational Elucidation of the Structural Basis of CXCR4 Antagonist Binding; 3.4 Drug Discovery Efforts by Virtual Ligand Screening Against Models and Structures of CXCR4; 3.5 Molecular Design and Optimization Studies Assisted by the Structures of CXCR4; 3.6 Computational Prediction of Small-Molecule Antagonist Binding to CCR5; 3.7 Drug Discovery Efforts by Virtual Ligand Screening Against Models and Structures of CCR5; 3.8 Model-Assisted Molecular Design and Optimization for CCR5 4 Allostery and Chemokine Receptors5 The Allosteric Vector; 5.1 Allosterism Along the Plane of the Membrane; 5.2 Guest Allosterism; 5.3 Cytosol-Directed Allosterism; 6 Challenges and Opportunities Faced in the Design of Allosteric Ligands for Chemokine Receptors; 6.1 Orthosteric Versus Allosteric; 6.2 ``Molecular Switches; 7 Recent Structural Insights into Chemokine Receptors; 8 Allosteric Modulators of Chemokine Receptors: From Bench-to-Clinic Challenges; 9 Conclusions; References; Exploring the CXCR3 Chemokine Receptor with Small-Molecule Antagonists and Agonists; 1 Introduction 4 Structure-Guided Understanding of Receptor Interactions with Chemokines5 Structure-Guided Understanding of Receptor Interactions with HIV gp120; 6 Structure-Guided Understanding of Receptor Dimers; 7 Structure-Based Design of Crystallographic Constructs for Chemokine Receptors; 8 Modeling of Other Chemokine Receptors by Homology with Existing Structures; 8 Conclusion; References; Allosteric Modulation of Chemokine Receptors; 1 Introduction; 2 Mechanism of Chemokine-Receptor Interactions; 3 Promiscuity of Chemokines and Their Receptors in Health and Disease 11 Reasons for the Clinical Failure of Chemokine Receptor Antagonists in Rheumatoid Arthritis12 Chemokine Receptors as Vehicles of Entry for HIV; 13 Inhibiting Viral Entry via CCR5 and CXCR4; 14 New Tricks for Old Drugs?; 15 Summary; References; Role of 3D Structures in Understanding, Predicting, and Designing Molecular Interactions in the Chemokine Receptor Family; 1 Introduction; 2 Chemokine Receptor Structures and Complexes to Date; 3 Structural Basis of Receptor Interactions with Small Molecules; 3.1 CXCR4 Interactions with Small Molecules and Peptides Preface; Contents; Chemokine Receptors in Allergy, Inflammation, and Infectious Disease; 1 Introduction; 2 The Role of Chemokines in Asthma; 3 Chemokine-Driven Eosinophil Recruitment in Asthma; 4 Targeting Eosinophil Chemokine Receptors ; 5 Chemokine-Driven Lymphocyte Recruitment in Asthma; 6 Targeting Lymphocyte Chemokine Receptors in Asthma; 7 Multiple Sclerosis; 8 Targeting Chemokine Receptors in Multiple Sclerosis; 9 Reasons for the Clinical Failure of Chemokine Receptor Antagonists in Multiple Sclerosis; 10 Rheumatoid Arthritis Front Matter....Pages i-vii Chemokine Receptors in Allergy, Inflammation, and Infectious Disease....Pages 1-39 Role of 3D Structures in Understanding, Predicting, and Designing Molecular Interactions in the Chemokine Receptor Family....Pages 41-85 Allosteric Modulation of Chemokine Receptors....Pages 87-117 Exploring the CXCR3 Chemokine Receptor with Small-Molecule Antagonists and Agonists....Pages 119-185 Selective and Dual Targeting of CCR2 and CCR5 Receptors: A Current Overview....Pages 187-241 Back Matter....Pages 243-245