New Insights from Crystallographic Data: Diversity of Structural Motifs and Molecular Recognition Properties between Groups of IDO1 Structures

ChemMedChem. 2020 May 19;15(10):891-899. doi: 10.1002/cmdc.202000116. Epub 2020 Apr 14.

Abstract

A large number of crystallographic structures of IDO1 in different ligand-bound and -unbound states have been disclosed over the last decade. Yet, only a few of them have been exploited for structure-based drug design (SBDD) campaigns. In this study, we analyzed the structural motifs and molecular-recognition properties of three groups of IDO1 structures: 1) structures containing the heme group and inhibitors in the catalytic site; 2) heme-free structures of IDO1; 3) substrate-bound structures of IDO1. The results suggest that unrelated conformations of the enzyme have been solved with different ligand-induced changes of secondary motifs that localize even in regions remote from the catalytic site. Moreover, the study identified an uncharted region of molecular-recognition space covered by IDO1 binding sites that could guide the selection of diverse structures for additional SBDD studies aimed at the identification of novel lead compounds with differentiated chemical scaffolds.

Keywords: IDO1; docking; kynurenine; molecular recognition; tryptophan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites / drug effects
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / antagonists & inhibitors*
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / chemistry
  • Indoleamine-Pyrrole 2,3,-Dioxygenase / metabolism
  • Ligands
  • Models, Molecular
  • Molecular Conformation
  • Protein Folding

Substances

  • Enzyme Inhibitors
  • IDO1 protein, human
  • Indoleamine-Pyrrole 2,3,-Dioxygenase
  • Ligands