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Substituted polyfluoroaryl interactions with an arginine side chain in galectin-3 are governed by steric-, desolvation and electronic conjugation effects

Kumar, Rohit LU ; Peterson, Kristoffer LU ; Misini Ignjatović, Majda LU ; Leffler, Hakon LU ; Ryde, Ulf LU ; Nilsson, Ulf J. LU and Logan, Derek T. LU (2019) In Organic and Biomolecular Chemistry 17(5). p.1081-1089
Abstract

In the β-d-galactopyranoside-binding protein galectin-3, synthetic inhibitors substituted at the 3-position of a thiodigalactoside core cause the formation of an aglycone binding pocket through the displacement of an arginine residue (Arg144) from its position in the apoprotein. To examine in detail the role of different molecular interactions in this pocket, we have synthesized a series of nine 3-(4-(2,3,5,6-tetrafluorophenyl)-1,2,3-triazol-1-yl)-thiogalactosides with different para substituents and measured their affinities to galectin-3 using a fluorescence polarization assay. High-resolution crystal structures (<1.3 Å) have been determined for five of the ligands in complex with the C-terminal domain of galectin-3. The binding... (More)

In the β-d-galactopyranoside-binding protein galectin-3, synthetic inhibitors substituted at the 3-position of a thiodigalactoside core cause the formation of an aglycone binding pocket through the displacement of an arginine residue (Arg144) from its position in the apoprotein. To examine in detail the role of different molecular interactions in this pocket, we have synthesized a series of nine 3-(4-(2,3,5,6-tetrafluorophenyl)-1,2,3-triazol-1-yl)-thiogalactosides with different para substituents and measured their affinities to galectin-3 using a fluorescence polarization assay. High-resolution crystal structures (<1.3 Å) have been determined for five of the ligands in complex with the C-terminal domain of galectin-3. The binding affinities are rationalised with the help of the three-dimensional structures and quantum-mechanical calculations. Three effects seem to be involved: Firstly, the binding pocket is too small for the largest ligands with ethyl and methyl. Secondly, for the other ligands, the affinity seems to be determined mainly by desolvation effects, disfavouring the polar substituents, but this is partly counteracted by the cation-π interaction with Arg144, which stacks on top of the substituted tetrafluorophenyl group in all complexes. The results provide detailed insight into interactions of fluorinated phenyl moieties with arginine-containing protein binding sites and the complex interplay of different energetic components in defining the binding affinity.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Organic and Biomolecular Chemistry
volume
17
issue
5
pages
9 pages
publisher
Royal Society of Chemistry
external identifiers
  • scopus:85060943845
ISSN
1477-0520
DOI
10.1039/c8ob02888e
language
English
LU publication?
yes
id
718992bf-c162-4461-b91f-eb2602e6d74d
date added to LUP
2019-02-12 11:53:25
date last changed
2019-03-05 04:32:43
@article{718992bf-c162-4461-b91f-eb2602e6d74d,
  abstract     = {<p>In the β-d-galactopyranoside-binding protein galectin-3, synthetic inhibitors substituted at the 3-position of a thiodigalactoside core cause the formation of an aglycone binding pocket through the displacement of an arginine residue (Arg144) from its position in the apoprotein. To examine in detail the role of different molecular interactions in this pocket, we have synthesized a series of nine 3-(4-(2,3,5,6-tetrafluorophenyl)-1,2,3-triazol-1-yl)-thiogalactosides with different para substituents and measured their affinities to galectin-3 using a fluorescence polarization assay. High-resolution crystal structures (&lt;1.3 Å) have been determined for five of the ligands in complex with the C-terminal domain of galectin-3. The binding affinities are rationalised with the help of the three-dimensional structures and quantum-mechanical calculations. Three effects seem to be involved: Firstly, the binding pocket is too small for the largest ligands with ethyl and methyl. Secondly, for the other ligands, the affinity seems to be determined mainly by desolvation effects, disfavouring the polar substituents, but this is partly counteracted by the cation-π interaction with Arg144, which stacks on top of the substituted tetrafluorophenyl group in all complexes. The results provide detailed insight into interactions of fluorinated phenyl moieties with arginine-containing protein binding sites and the complex interplay of different energetic components in defining the binding affinity.</p>},
  author       = {Kumar, Rohit and Peterson, Kristoffer and Misini Ignjatović, Majda and Leffler, Hakon and Ryde, Ulf and Nilsson, Ulf J. and Logan, Derek T.},
  issn         = {1477-0520},
  language     = {eng},
  month        = {01},
  number       = {5},
  pages        = {1081--1089},
  publisher    = {Royal Society of Chemistry},
  series       = {Organic and Biomolecular Chemistry},
  title        = {Substituted polyfluoroaryl interactions with an arginine side chain in galectin-3 are governed by steric-, desolvation and electronic conjugation effects},
  url          = {http://dx.doi.org/10.1039/c8ob02888e},
  volume       = {17},
  year         = {2019},
}