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Protein-Ligand Interactions and Drug Design pp 73–88Cite as

Binding Mode Prediction and Virtual Screening Applications by Covalent Docking

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

Abstract

The mechanism of action of covalent drugs involves the formation of a bond between their electrophilic warhead group and a nucleophilic residue of the protein target. The recent advances in covalent drug discovery have accelerated the development of computational tools for the design and characterization of covalent binders. Covalent docking algorithms can predict the binding mode of covalent ligands by modeling the bonds and interactions formed at the reaction site. Their scoring functions can estimate the relative binding affinity of ligands towards the target of interest, thus allowing virtual screening of compound libraries. However, most of the scoring schemes have no specific terms for the bond formation, and therefore it prevents the direct comparison of warheads with different intrinsic reactivity. Herein, we describe a protocol for the binding mode prediction of covalent ligands, a typical virtual screening of compound sets with a single warhead chemistry, and an alternative approach to screen libraries that include various warhead types, as applied in recently validated studies.

Key words

  • Covalent docking
  • Targeted covalent inhibitors
  • Binding mode prediction
  • Virtual screening
  • Warhead
  • Reactivity

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Acknowledgments

The research was supported by the Marie Sklodowska Curie Action (MSCA) Innovative Training Network grant FRAGNET and by the National Research Development and Innovation Office (grant number SNN_17 125496).

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Authors and Affiliations

  1. Medicinal Chemistry Research Group, Research Centre for Natural Sciences, Budapest, Hungary

    Andrea Scarpino, György G. Ferenczy & György M. Keserű

Authors
  1. Andrea Scarpino
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  2. György G. Ferenczy
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  3. György M. Keserű
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Corresponding author

Correspondence to György M. Keserű .

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Editors and Affiliations

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

    Dr. Flavio Ballante

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Scarpino, A., Ferenczy, G.G., Keserű, G.M. (2021). Binding Mode Prediction and Virtual Screening Applications by Covalent Docking. 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_4

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  • DOI: https://doi.org/10.1007/978-1-0716-1209-5_4

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-1208-8

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