Structural Biology in Drug Discovery

With the most comprehensive and up-to-date overview of structure-based drug discovery covering both experimental and computational approaches, Structural Biology in Drug Discovery: Methods, Techniques, and Practices describes principles, methods, applications, and emerging paradigms of structural biology as a tool for more efficient drug development. Coverage includes successful examples, academic and industry insights, novel concepts, and advances in a rapidly evolving field.

The combined chapters, by authors writing from the frontlines of structural biology and drug discovery, give readers a valuable reference and resource that:

• Presents the benefits, limitations, and potentiality of major techniques in the field such as X-ray crystallography, NMR, neutron crystallography, cryo-EM, mass spectrometry and other biophysical techniques, and computational structural biology
• Includes detailed chapters on druggability, allostery, complementary use of thermodynamic and kinetic information, and powerful approaches such as structural chemogenomics and fragment-based drug design
• Emphasizes the need for the in-depth biophysical characterization of protein targets as well as of therapeutic proteins, and for a thorough quality assessment of experimental structures
• Illustrates advances in the field of established therapeutic targets like kinases, serine proteinases, GPCRs, and epigenetic proteins, and of more challenging ones like protein-protein interactions and intrinsically disordered proteins

List of Contributors

Preface

Chapter 01: The Evolving Role of Structural Biology in Drug Discovery

Chapter 02: A Structural View on Druggability: Experimental and Computational Approaches

Chapter 03: Structural Chemogenomics: Profiling Protein–Ligand Interactions in Polypharmacological Space

Chapter 04: Fragment-Based Ligand Discovery

Chapter 05: Combining Structural, Thermodynamic and Kinetic Information to Drive Hit-to-Lead Progression

Chapter 06: Allostery as Structure-Encoded Collective Dynamics: Significance in Drug Design

Chapter 07: Biophysical Assessment of Target Protein Quality in Structure-Based Drug discovery

Chapter 08: An Industrial Perspective on Protein-Ligand Complex Crystallization

Chapter 09: Membrane Protein Crystallization

Chapter 10: High-throughput Macromolecular Crystallography in Drug Discovery: Evolving in the Midst of Revolutions

Chapter 11: Assessment of Crystallographic Structure Quality and Protein – Ligand Complex Structure Validation

Chapter 12: Complementary Information from Neutron Crystallography Studies

Chapter 13: Determination of Protein Structure and Dynamics by NMR: State of the Art and Application to the Characterization of Biotherapeutics

Chapter 14: NMR Studies of Protein – Small Molecule Interactions for Drug Discovery

Chapter 15: Computational Structural Biology for Drug Discovery: Power and Limitations

Chapter 16: The Role of Structural Biology in Kinase Inhibitors Drug Discovery Success

Chapter 17: Serine Proteinases from the Blood Coagulation Cascade

Chapter 18: Epigenetic Proteins as Emerging Drug Targets

Chapter 19: Impact of Recently Determined Crystallographic Structures of GPCRs on Drug Discovery

Chapter 20: Targeting Protein–Protein Interactions Perspective

Chapter 21: Mass Spectrometry-Based Strategies for Therapeutic Antibodies Extensive Characterization and Optimization (OptimAbs)

Chapter 22: Integrating Evolution of Drug Resistance into Drug Discovery: Lessons from the Viral Proteases of HIV-1 and HCV

Chapter 23: A Comprehensive Review on Mycobacterium Tuberculosis Targets and Drug Development from a Structural Perspective

Chapter 24: Using Crystal Structures of Drug-Metabolizing Enzymes in Mechanism-Based Modeling for Drug Design

Chapter 25: Intrinsically Disordered Proteins (IDPs): Targets for the Future?

Chapter 26: Cryo-electron Microscopy as a Tool for Drug Discovery in the Context of Integrative Structural Biology

Chapter 27: Application of Hard-X-ray Free-electron Lasers for Static and Dynamic Processes in Structural Biology

"The book ... is a surprisingly comprehensive, monumental collection of chapters by a number of researchers in the field of drug discovery. ... [Editor Jean-Paul] Renaud was able to see the broad crucial aspects of the field and therefore able to invite excellent scientists to coauthor this book and cover so many aspects and in so much depth." -- Crystallography Reviews, March 2022

JEAN-PAUL RENAUD, PhD, is cofounder and President & Chief Scientific Officer at Urania Therapeutics (formerly RiboStruct), which focuses on rational drug design targeting the human ribosome. Previously, he was cofounder and Chief Scientific Officer at NovAliX and CNRS Research Director in the Structural Biology and Genomics Department at the Institute of Genetics and Molecular and Cellular Biology. Dr Renaud has over 30 years of research experience, along with 48 articles, 4 book chapters and 3 patents to his credit. He also initiated and is the Chairman and Scientific Organizer of the NovAliX Conferences "Biophysics in Drug Discovery".

Structure-based drug discovery exploits the knowledge of the three-dimensional framework of biological molecules to enhance the process and outcome of drug design and development. Scientists can utilize modern structural biology techniques to characterize new therapeutic targets and develop efficient new drugs. Over the last few years, there have been significant improvements and advances in the field, leading to faster and more effective drug development at the preclinical stage. Today, a number of drugs have been derived from structure-based design programs and scientists continue to discover breakthrough methods in this fast-growing field.

With the most comprehensive and up-to-date overview of structure-based drug discovery covering mostly experimental but also computational approaches, Structural Biology in Drug Discovery: Methods, Techniques, and Practices describes principles, methods, applications, and emerging paradigms of structural biology as a tool for more efficient drug development. Coverage includes successful examples, academic and industry insights, novel concepts, and advances in a rapidly evolving field.

The combined chapters, by authors writing from the frontlines of structural biology and drug discovery, give readers a valuable reference and resource that:

• Presents the benefits, limitations, and potentiality of major techniques in the field such as X-ray crystallography, NMR, neutron crystallography, cryo-EM, mass spectrometry and other biophysical techniques, and computational structural biology
• Includes detailed chapters on druggability, allostery, complementary use of thermodynamic and kinetic information, and powerful approaches such as structural chemogenomics and fragment-based drug design
• Emphasizes the need for the in-depth biophysical characterization of protein targets as well as of therapeutic proteins, and for a thorough quality assessment of experimental structures
• Illustrates advances in the field of established therapeutic targets like kinases, serine proteinases, GPCRs, and epigenetic proteins, and of more challenging ones like protein-protein interactions and intrinsically disordered proteins