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Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls

Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacolo...

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Autores principales: Mammoli, Andrea, Bianconi, Elisa, Ruta, Luana, Riccio, Alessandra, Bigiotti, Carlo, Souma, Maria, Carotti, Andrea, Rossini, Sofia, Suvieri, Chiara, Pallotta, Maria Teresa, Grohmann, Ursula, Camaioni, Emidio, Macchiarulo, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999677/
https://www.ncbi.nlm.nih.gov/pubmed/35409342
http://dx.doi.org/10.3390/ijms23073981
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author Mammoli, Andrea
Bianconi, Elisa
Ruta, Luana
Riccio, Alessandra
Bigiotti, Carlo
Souma, Maria
Carotti, Andrea
Rossini, Sofia
Suvieri, Chiara
Pallotta, Maria Teresa
Grohmann, Ursula
Camaioni, Emidio
Macchiarulo, Antonio
author_facet Mammoli, Andrea
Bianconi, Elisa
Ruta, Luana
Riccio, Alessandra
Bigiotti, Carlo
Souma, Maria
Carotti, Andrea
Rossini, Sofia
Suvieri, Chiara
Pallotta, Maria Teresa
Grohmann, Ursula
Camaioni, Emidio
Macchiarulo, Antonio
author_sort Mammoli, Andrea
collection PubMed
description Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns. In this work, we report a screening campaign of a fragment library of compounds, grounding on the use of three distinct conformations of IDO1 that recapitulate its structural plasticity to some extent. Results are instrumental to discuss tips and pitfalls that, due to the large plasticity of the enzyme, may influence the identification of novel and differentiated chemical scaffolds of IDO1 ligands in structure-based screening campaigns.
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spelling pubmed-89996772022-04-12 Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls Mammoli, Andrea Bianconi, Elisa Ruta, Luana Riccio, Alessandra Bigiotti, Carlo Souma, Maria Carotti, Andrea Rossini, Sofia Suvieri, Chiara Pallotta, Maria Teresa Grohmann, Ursula Camaioni, Emidio Macchiarulo, Antonio Int J Mol Sci Article Over the last two decades, indoleamine 2,3-dioxygenase 1 (IDO1) has attracted wide interest as a key player in immune regulation, fostering the design and development of small molecule inhibitors to restore immune response in tumor immunity. In this framework, biochemical, structural, and pharmacological studies have unveiled peculiar structural plasticity of IDO1, with different conformations and functional states that are coupled to fine regulation of its catalytic activity and non-enzymic functions. The large plasticity of IDO1 may affect its ligand recognition process, generating bias in structure-based drug design campaigns. In this work, we report a screening campaign of a fragment library of compounds, grounding on the use of three distinct conformations of IDO1 that recapitulate its structural plasticity to some extent. Results are instrumental to discuss tips and pitfalls that, due to the large plasticity of the enzyme, may influence the identification of novel and differentiated chemical scaffolds of IDO1 ligands in structure-based screening campaigns. MDPI 2022-04-02 /pmc/articles/PMC8999677/ /pubmed/35409342 http://dx.doi.org/10.3390/ijms23073981 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Mammoli, Andrea
Bianconi, Elisa
Ruta, Luana
Riccio, Alessandra
Bigiotti, Carlo
Souma, Maria
Carotti, Andrea
Rossini, Sofia
Suvieri, Chiara
Pallotta, Maria Teresa
Grohmann, Ursula
Camaioni, Emidio
Macchiarulo, Antonio
Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls
title Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls
title_full Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls
title_fullStr Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls
title_full_unstemmed Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls
title_short Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls
title_sort critical assessment of a structure-based screening campaign for ido1 inhibitors: tips and pitfalls
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8999677/
https://www.ncbi.nlm.nih.gov/pubmed/35409342
http://dx.doi.org/10.3390/ijms23073981
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