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

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Computational Methods for GPCR Drug Discovery

Part of the book series: Methods in Molecular Biology ((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.

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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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Authors and Affiliations

  1. Evotec (UK) Ltd., 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire, OX14 4RZ, UK

    Alexander Heifetz, Michelle Southey, Inaki Morao & Mike J. Bodkin

  2. Division of Biosciences, Research Department of Structural and Molecular Biology, Institute of Structural and Molecular Biology, University College London, London, WC1E 6BT, UK

    Alexander Heifetz

  3. Division of Biosciences, Research Department of Structural and Molecular Biology, University College London, Darwin Building, Gower Street, London, WC1E 6BT, UK

    Andrea Townsend-Nicholson

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  1. Alexander Heifetz
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  2. Michelle Southey
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  3. Inaki Morao
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  4. Andrea Townsend-Nicholson
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  5. Mike J. Bodkin
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Correspondence to Alexander Heifetz .

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  1. Evotec (UK) Ltd., Abingdon, Oxfordshire, United Kingdom

    Alexander Heifetz

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Heifetz, A., Southey, M., Morao, I., Townsend-Nicholson, A., Bodkin, M.J. (2018). Computational Methods Used in Hit-to-Lead and Lead Optimization Stages of Structure-Based Drug Discovery. In: Heifetz, A. (eds) Computational Methods for GPCR Drug Discovery. Methods in Molecular Biology, vol 1705. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4939-7465-8_19

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  • DOI: https://doi.org/10.1007/978-1-4939-7465-8_19

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  • Publisher Name: Humana Press, New York, NY

  • Print ISBN: 978-1-4939-7464-1

  • Online ISBN: 978-1-4939-7465-8

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