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Specificities of Protein Homology Modeling for Allosteric Drug Design

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Homology Modeling

Part of the book series: Methods in Molecular Biology ((MIMB,volume 2627))

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Abstract

The allosteric binding sites are usually located in the flexible areas of proteins, which are hardly visible in the crystal structures. However, there are notable exceptions like allosteric sites in receptors in class B and C of GPCRs, which are located within a well-defined bundle of transmembrane helices. Class B and C evolved from class A and even after swapping of orthosteric and allosteric sites the central binding site persisted and it can be used for easy design of allosteric drugs. However, studying the ligand binding to the allosteric sites in the most populated class A of GPCRs is still a challenge, since they are located mostly in unresolved parts of the receptor’s structure, and especially N-terminus. This chapter provides an example of cannabinoid CB1 receptor N-terminal homology modeling, ligand-guided modeling of the allosteric site in GABA receptor, as well as C-linker modeling in the potassium ion channels where the allosteric phospholipid ligand PIP2 is bound.

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Authors and Affiliations

  1. Faculty of Chemistry, Biological and Chemical Research Centre, University of Warsaw, Warsaw, Poland

    Jakub Jakowiecki, Urszula Orzeł, Aleksandra Gliździnska, Mariusz Możajew & Sławomir Filipek

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  1. Jakub Jakowiecki
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  2. Urszula Orzeł
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  3. Aleksandra Gliździnska
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  4. Mariusz Możajew
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  5. Sławomir Filipek
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Correspondence to Sławomir Filipek .

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  1. Faculty of Chemistry, University of Warsaw, Warsaw, Poland

    Sławomir Filipek

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Jakowiecki, J., Orzeł, U., Gliździnska, A., Możajew, M., Filipek, S. (2023). Specificities of Protein Homology Modeling for Allosteric Drug Design. In: Filipek, S. (eds) Homology Modeling. Methods in Molecular Biology, vol 2627. Humana, New York, NY. https://doi.org/10.1007/978-1-0716-2974-1_19

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  • DOI: https://doi.org/10.1007/978-1-0716-2974-1_19

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  • Publisher Name: Humana, New York, NY

  • Print ISBN: 978-1-0716-2973-4

  • Online ISBN: 978-1-0716-2974-1

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