Critical Assessment of a Structure-Based Screening Campaign for IDO1 Inhibitors: Tips and Pitfalls.
biophysics
fragment-based drug design
molecular docking
thermophoresis
virtual screening
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
02 Apr 2022
02 Apr 2022
Historique:
received:
10
03
2022
revised:
30
03
2022
accepted:
31
03
2022
entrez:
12
4
2022
pubmed:
13
4
2022
medline:
14
4
2022
Statut:
epublish
Résumé
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.
Identifiants
pubmed: 35409342
pii: ijms23073981
doi: 10.3390/ijms23073981
pmc: PMC8999677
pii:
doi:
Substances chimiques
Enzyme Inhibitors
0
Indoleamine-Pyrrole 2,3,-Dioxygenase
0
Ligands
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : European Research Council
ID : ERC-2013-AdG-338954-DIDO
Pays : International
Organisme : European Research Council
ID : ERC-2017-PoC-780807-DIDO-MS
Pays : International
Organisme : European Research Council
ID : ERC-2019-PoC-899838-ENHANCIDO
Pays : International
Organisme : University of Perugia
ID : Ricerca di base 2020 and 2021
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