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Tracking Hidden Binding Pockets Along the Molecular Recognition Path of l ‐Trp to Indoleamine 2,3‐Dioxygenase 1
Author(s) -
Greco Francesco A.,
Albini Elisa,
Coletti Alice,
Dolciami Daniela,
Carotti Andrea,
Orabona Ciriana,
Grohmann Ursula,
Macchiarulo Antonio
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900529
Subject(s) - indoleamine 2,3 dioxygenase , chemistry , kynurenine , kynurenine pathway , tryptophan , enzyme , stereochemistry , biochemistry , mutagenesis , dioxygenase , computational biology , biophysics , biology , gene , mutant , amino acid
Indoleamine 2,3‐dioxygenase 1 (IDO1) catalyzes the oxidative cleavage of l ‐Tryptophan ( l ‐Trp) to yield N‐formyl‐kynurenine in the first and rate limiting step of the kynurenine pathway. Bioactive metabolites, involved in the regulation of important immunological responses and neurological processes, are then produced by downstream enzymes along the pathway. Inhibitors of IDO1 are being designed and developed as therapeutic agents for immuno‐oncology. In this work, we investigated the molecular recognition path of l ‐Trp to IDO1, integrating biophysical methods with supervised molecular dynamics (suMD) and mutagenesis experiments. Results allowed disclosing for the first time high and low dissociation constants of l ‐Trp to IDO1, and the presence of a metastable interaction site located at the upper part of a channel whose borders are defined by the EF‐loop and the C‐terminal part of the JK‐loop. Collectively, our results provide new clues for the design of next‐generation IDO1 ligands.