Computational Methods for GPCR Drug Discovery

Description

This volume looks at modern computational strategies and techniques used in GPCR drug discovery including structure and ligand-based approaches and cheminformatics. The chapters in this book describe how these approaches can be applied to address key drug discovery issues, such as receptor structure modelling, function and dynamics, prediction of protein-water-ligand interactions and binding kinetics, free energy of binding, interconversion between agonists and antagonists, deorphanization of GPCRs, and the discovery of biased and allosteric modulators. Written in the highly successful Methods in Molecular Biology series format, chapters include introductions to their respective topics, lists of the necessary software and tools, step-by-step, readily reproducible modelling protocols, and tips on troubleshooting and avoiding known pitfalls. Cutting-edge and unique,Computational Methods for GPCR Drug Discovery is a valuable resource for structural and molecular biologists, computational and medicinal chemists, pharmacologists, and drug designers. Front Matter ....Pages i-xi Current and Future Challenges in GPCR Drug Discovery (Sid Topiol)....Pages 1-21 Characterization of Ligand Binding to GPCRs Through Computational Methods (Silvana Vasile, Mauricio Esguerra, Willem Jespers, Ana Oliveira, Jessica Sallander, Johan Åqvist et al.)....Pages 23-44 Breakthrough in GPCR Crystallography and Its Impact on Computer-Aided Drug Design (Antonella Ciancetta, Kenneth A. Jacobson)....Pages 45-72 A Structural Framework for GPCR Chemogenomics: What’s In a Residue Number? (Márton Vass, Albert J. Kooistra, Stefan Verhoeven, David Gloriam, Iwan J. P. de Esch, Chris de Graaf)....Pages 73-113 GPCR Homology Model Generation for Lead Optimization (Christofer S. Tautermann)....Pages 115-131 GPCRs: What Can We Learn from Molecular Dynamics Simulations? (Naushad Velgy, George Hedger, Philip C. Biggin)....Pages 133-158 Methods of Exploring Protein–Ligand Interactions to Guide Medicinal Chemistry Efforts (Paul Labute)....Pages 159-177 Exploring GPCR-Ligand Interactions with the Fragment Molecular Orbital (FMO) Method (Ewa I. Chudyk, Laurie Sarrat, Matteo Aldeghi, Dmitri G. Fedorov, Mike J. Bodkin, Tim James et al.)....Pages 179-195 Molecular Basis of Ligand Dissociation from G Protein-Coupled Receptors and Predicting Residence Time (Dong Guo, Adriaan P. IJzerman)....Pages 197-206 Methodologies for the Examination of Water in GPCRs (Andrea Bortolato, Benjamin G. Tehan, Robert T. Smith, Jonathan S. Mason)....Pages 207-232 Methods for Virtual Screening of GPCR Targets: Approaches and Challenges (Jason B. Cross)....Pages 233-264 Approaches for Differentiation and Interconverting GPCR Agonists and Antagonists (Przemysław Miszta, Jakub Jakowiecki, Ewelina Rutkowska, Maria Turant, Dorota Latek, Sławomir Filipek)....Pages 265-296 Opportunities and Challenges in the Discovery of Allosteric Modulators of GPCRs (Damian Bartuzi, Agnieszka A. Kaczor, Dariusz Matosiuk)....Pages 297-319 Challenges and Opportunities in Drug Discovery of Biased Ligands (Ismael Rodríguez-Espigares, Agnieszka A. Kaczor, Tomasz Maciej Stepniewski, Jana Selent)....Pages 321-334 Synergistic Use of GPCR Modeling and SDM Experiments to Understand Ligand Binding (Andrew Potterton, Alexander Heifetz, Andrea Townsend-Nicholson)....Pages 335-343 Computational Support of Medicinal Chemistry in Industrial Settings (Daniel F. Ortwine)....Pages 345-350 Investigating Small-Molecule Ligand Binding to G Protein-Coupled Receptors with Biased or Unbiased Molecular Dynamics Simulations (Kristen A. Marino, Marta Filizola)....Pages 351-364 Ligand-Based Methods in GPCR Computer-Aided Drug Design (Paul C. D. Hawkins, Gunther Stahl)....Pages 365-374 Computational Methods Used in Hit-to-Lead and Lead Optimization Stages of Structure-Based Drug Discovery (Alexander Heifetz, Michelle Southey, Inaki Morao, Andrea Townsend-Nicholson, Mike J. Bodkin)....Pages 375-394 Cheminformatics in the Service of GPCR Drug Discovery (Tim James)....Pages 395-411 Modeling and Deorphanization of Orphan GPCRs (Constantino Diaz, Patricia Angelloz-Nicoud, Emilie Pihan)....Pages 413-429 Back Matter ....Pages 431-436