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A Protocol to Use Comparative Binding Energy Analysis to Estimate Drug-Target Residence Time

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Protein-Ligand Interactions and Drug Design

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2266))

Abstract

Comparative Binding Energy (COMBINE) analysis is an approach for deriving a target-specific scoring function to compute binding free energy, drug-binding kinetics, or a related property by exploiting the information contained in the three-dimensional structures of receptor–ligand complexes. Here, we describe the process of setting up and running COMBINE analysis to derive a Quantitative Structure-Kinetics Relationship (QSKR) for the dissociation rate constants (koff) of inhibitors of a drug target. The derived QSKR model can be used to estimate residence times (τ, τ=1/koff) for similar inhibitors binding to the same target, and it can also help to identify key receptor–ligand interactions that distinguish inhibitors with short and long residence times. Herein, we demonstrate the protocol for the application of COMBINE analysis on a dataset of 70 inhibitors of heat shock protein 90 (HSP90) belonging to 11 different chemical classes. The procedure is generally applicable to any drug target with known structural information on its complexes with inhibitors.

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Acknowledgments

This work was supported by the EU/EFPIA Innovative Medicines Initiative (IMI) Joint Undertaking, K4DD (Grant No. 115366), by the Klaus Tschira Foundation and by a Capes-Humboldt postdoctoral scholarship to A N-A (Capes process number 88881.162167/2017-01). G.K.G. also thanks HGSMathComp Graduate School, Heidelberg University for providing academic and administrative support.

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Authors and Affiliations

  1. Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies, Heidelberg, Germany

    Gaurav K. Ganotra, Ariane Nunes-Alves & Rebecca C. Wade

  2. Center for Molecular Biology (ZMBH), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg, Germany

    Ariane Nunes-Alves & Rebecca C. Wade

  3. Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, Heidelberg, Germany

    Rebecca C. Wade

Authors
  1. Gaurav K. Ganotra
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  2. Ariane Nunes-Alves
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  3. Rebecca C. Wade
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Corresponding author

Correspondence to Rebecca C. Wade .

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Editors and Affiliations

  1. Department of Cell and Molecular Biology, Uppsala University, Uppsala, Sweden

    Flavio Ballante

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Ganotra, G.K., Nunes-Alves, A., Wade, R.C. (2021). A Protocol to Use Comparative Binding Energy Analysis to Estimate Drug-Target Residence Time. In: Ballante, F. (eds) Protein-Ligand Interactions and Drug Design. Methods in Molecular Biology, vol 2266. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-1209-5_10

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  • DOI: https://doi.org/10.1007/978-1-0716-1209-5_10

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1208-8

  • Online ISBN: 978-1-0716-1209-5

  • eBook Packages: Springer Protocols

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