Chapter 16
Rational Design of PDZ Domain Inhibitors: Discovery of
Small Organic Compounds Targeting PDZ Domains
Laurent Hoffer, Philippe Roche, and Xavier Morelli
Abstract
PDZ domains, which belong to protein–protein interaction networks, are critical for regulating important
biological processes such as scaffolding, trafficking, and signaling cascades. Interfering with PDZ-mediated
interactions could affect these numerous biological processes. Thus, PDZ domains have emerged as
promising targets to decipher biological phenomena and potentially treat cancer and neurological diseases.
In this minireview, we focus on the discovery and design of small molecule inhibitors to modulate PDZ
domains. These compounds interfere with endogenous protein partners from the PDZ domain by binding
at the protein–protein interface. While peptides or peptidomimetic ligands were described to modulate
PDZ domains, the focus of this review is on small organic compounds.
Key words PDZ domain, PDZ inhibitors, Rational design, Screening, Molecular modeling
1 Introduction
Postsynaptic density protein 95/Drosophila disc large tumor suppressor/Zonula occludens 1 (PDZ) proteins are a family of proteins that contain at least one PDZ domain. The binding of protein
partners to PDZ domains mediates various processes, such as the
formation of protein networks, the immobilization of these proteins in the correct cellular compartment and the ability of promoting scaffolding, trafficking, and signaling events [1–4].
The PDZ domain is a common structural domain of approximately 90 amino acids found in signaling proteins of many organisms. The global structure is conserved and usually consists of 5–6
β-strands and 2 α-helixes. In general, PDZ domains have a shallow
binding site located between one β-strand and one α-helix that
recognizes the C-terminus (terminal carboxylate and last residues)
of their protein partners (Fig. 1).
C-terminal residues from a protein partner form an additional
antiparallel β-sheet by interacting with residues of the PDZ domain
through hydrogen bonds with backbone atoms. In addition, the
Jean-Paul Borg (ed.), PDZ Mediated Interactions: Methods and Protocols, Methods in Molecular Biology, vol. 2256,
https://doi.org/10.1007/978-1-0716-1166-1_16, © Springer Science+Business Media, LLC, part of Springer Nature 2021
277
Rational Design of PDZ Domain Inhibitors: Discovery of
Small Organic Compounds Targeting PDZ Domains
Laurent Hoffer, Philippe Roche, and Xavier Morelli
Abstract
PDZ domains, which belong to protein–protein interaction networks, are critical for regulating important
biological processes such as scaffolding, trafficking, and signaling cascades. Interfering with PDZ-mediated
interactions could affect these numerous biological processes. Thus, PDZ domains have emerged as
promising targets to decipher biological phenomena and potentially treat cancer and neurological diseases.
In this minireview, we focus on the discovery and design of small molecule inhibitors to modulate PDZ
domains. These compounds interfere with endogenous protein partners from the PDZ domain by binding
at the protein–protein interface. While peptides or peptidomimetic ligands were described to modulate
PDZ domains, the focus of this review is on small organic compounds.
Key words PDZ domain, PDZ inhibitors, Rational design, Screening, Molecular modeling
1 Introduction
Postsynaptic density protein 95/Drosophila disc large tumor suppressor/Zonula occludens 1 (PDZ) proteins are a family of proteins that contain at least one PDZ domain. The binding of protein
partners to PDZ domains mediates various processes, such as the
formation of protein networks, the immobilization of these proteins in the correct cellular compartment and the ability of promoting scaffolding, trafficking, and signaling events [1–4].
The PDZ domain is a common structural domain of approximately 90 amino acids found in signaling proteins of many organisms. The global structure is conserved and usually consists of 5–6
β-strands and 2 α-helixes. In general, PDZ domains have a shallow
binding site located between one β-strand and one α-helix that
recognizes the C-terminus (terminal carboxylate and last residues)
of their protein partners (Fig. 1).
C-terminal residues from a protein partner form an additional
antiparallel β-sheet by interacting with residues of the PDZ domain
through hydrogen bonds with backbone atoms. In addition, the
Jean-Paul Borg (ed.), PDZ Mediated Interactions: Methods and Protocols, Methods in Molecular Biology, vol. 2256,
https://doi.org/10.1007/978-1-0716-1166-1_16, © Springer Science+Business Media, LLC, part of Springer Nature 2021
277