Computational Methods Used in Hit-to-Lead and Lead Optimization Stages of Structure-Based Drug Discovery

• Published in: Methods in molecular biology (Clifton, N.J.) Vol. 1705; p. 375
• Main Authors: Heifetz, Alexander, Southey, Michelle, Morao, Inaki, Townsend-Nicholson, Andrea, Bodkin, Mike J
• Format: Journal Article
• Language: English
• Published: United States 01.01.2018
• Subjects: Computational Biology - methods; Computer Simulation; Drug Discovery - methods; Ligands; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Protein Binding; Quantitative Structure-Activity Relationship; Receptors, G-Protein-Coupled - chemistry; Receptors, G-Protein-Coupled - metabolism; Software; Water - chemistry; Workflow; G protein-coupled receptor; Structure-based drug design; Simulation; Hit-to-lead; Lead optimization; Molecular dynamics; Docking
• ISSN: 1940-6029
• DOI: 10.1007/978-1-4939-7465-8_19

GPCR modeling approaches are widely used in the hit-to-lead (H2L) and lead optimization (LO) stages of drug discovery. The aims of these modeling approaches are to predict the 3D structures of the receptor-ligand complexes, to explore the key interactions between the receptor and the ligand and to utilize these insights in the design of new molecules with improved binding, selectivity or other pharmacological properties. In this book chapter, we present a brief survey of key computational approaches integrated with hierarchical GPCR modeling protocol (HGMP) used in hit-to-lead (H2L) and in lead optimization (LO) stages of structure-based drug discovery (SBDD). We outline the differences in modeling strategies used in H2L and LO of SBDD and illustrate how these tools have been applied in three drug discovery projects.