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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
Protocol
Part of the Methods in Molecular Biology book series (MIMB, volume 1705)

Abstract

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.

Key words

Structure-based drug design Molecular dynamics Simulation Hit-to-lead Lead optimization G protein-coupled receptor Docking 

Notes

Acknowledgment

A.H. and A.T.-N. would like to acknowledge the support of EU H2020 CompBioMed project (http://www.compbiomed.eu/) and the BBSRC Flexible Interchanger Programme project (BB/P004245/1).

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Copyright information

© Springer Science+Business Media LLC 2018

Authors and Affiliations

  • Alexander Heifetz
    • 1
    • 2
  • Michelle Southey
    • 1
  • Inaki Morao
    • 1
  • Andrea Townsend-Nicholson
    • 3
  • Mike J. Bodkin
    • 1
  1. 1.Evotec (UK) Ltd.AbingdonUK
  2. 2.Division of Biosciences, Research Department of Structural and Molecular BiologyInstitute of Structural and Molecular Biology, University College LondonLondonUK
  3. 3.Division of Biosciences, Research Department of Structural and Molecular BiologyUniversity College LondonLondonUK

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