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Structure and Energetics of Ligand–Fluorine Interactions with Galectin-3 Backbone and Side-Chain Amides : Insight into Solvation Effects and Multipolar Interactions

Kumar, Rohit LU ; Ignjatović, Majda Misini LU ; Peterson, Kristoffer LU ; Olsson, Martin LU ; Leffler, Hakon LU ; Ryde, Ulf LU ; Nilsson, Ulf J. LU and Logan, Derek T. LU (2019) In ChemMedChem
Abstract

Multipolar fluorine–amide interactions with backbone and side-chain amides have been described as important for protein–ligand interactions and have been used to improve the potency of synthetic inhibitors. In this study, fluorine interactions within a well-defined binding pocket on galectin-3 were investigated systematically using phenyltriazolyl-thiogalactosides fluorinated singly or multiply at various positions on the phenyl ring. X-ray structures of the C-terminal domain of galectin-3 in complex with eight of these ligands revealed potential orthogonal fluorine–amide interactions with backbone amides and one with a side-chain amide. The two interactions involving main-chain amides seem to have a strong influence on affinity as... (More)

Multipolar fluorine–amide interactions with backbone and side-chain amides have been described as important for protein–ligand interactions and have been used to improve the potency of synthetic inhibitors. In this study, fluorine interactions within a well-defined binding pocket on galectin-3 were investigated systematically using phenyltriazolyl-thiogalactosides fluorinated singly or multiply at various positions on the phenyl ring. X-ray structures of the C-terminal domain of galectin-3 in complex with eight of these ligands revealed potential orthogonal fluorine–amide interactions with backbone amides and one with a side-chain amide. The two interactions involving main-chain amides seem to have a strong influence on affinity as determined by fluorescence anisotropy. In contrast, the interaction with the side-chain amide did not influence affinity. Quantum mechanics calculations were used to analyze the relative contributions of these interactions to the binding energies. No clear correlation could be found between the relative energies of the fluorine–main-chain amide interactions and the overall binding energy. Instead, dispersion and desolvation effects play a larger role. The results confirm that the contribution of fluorine–amide interactions to protein–ligand interactions cannot simply be predicted, on geometrical considerations alone, but require careful consideration of the energetic components.

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author
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
fluorine–amide interactions, galectin-3, medicinal chemistry, protein–ligand interactions, quantum mechanics
in
ChemMedChem
publisher
Wiley-Blackwell
external identifiers
  • scopus:85068916633
ISSN
1860-7179
DOI
10.1002/cmdc.201900293
language
English
LU publication?
yes
id
7742850c-7039-4d15-a5ab-56552254fb4b
date added to LUP
2019-07-24 11:42:14
date last changed
2019-08-28 04:57:16
@article{7742850c-7039-4d15-a5ab-56552254fb4b,
  abstract     = {<p>Multipolar fluorine–amide interactions with backbone and side-chain amides have been described as important for protein–ligand interactions and have been used to improve the potency of synthetic inhibitors. In this study, fluorine interactions within a well-defined binding pocket on galectin-3 were investigated systematically using phenyltriazolyl-thiogalactosides fluorinated singly or multiply at various positions on the phenyl ring. X-ray structures of the C-terminal domain of galectin-3 in complex with eight of these ligands revealed potential orthogonal fluorine–amide interactions with backbone amides and one with a side-chain amide. The two interactions involving main-chain amides seem to have a strong influence on affinity as determined by fluorescence anisotropy. In contrast, the interaction with the side-chain amide did not influence affinity. Quantum mechanics calculations were used to analyze the relative contributions of these interactions to the binding energies. No clear correlation could be found between the relative energies of the fluorine–main-chain amide interactions and the overall binding energy. Instead, dispersion and desolvation effects play a larger role. The results confirm that the contribution of fluorine–amide interactions to protein–ligand interactions cannot simply be predicted, on geometrical considerations alone, but require careful consideration of the energetic components.</p>},
  author       = {Kumar, Rohit and Ignjatović, Majda Misini and Peterson, Kristoffer and Olsson, Martin and Leffler, Hakon and Ryde, Ulf and Nilsson, Ulf J. and Logan, Derek T.},
  issn         = {1860-7179},
  keyword      = {fluorine–amide interactions,galectin-3,medicinal chemistry,protein–ligand interactions,quantum mechanics},
  language     = {eng},
  month        = {06},
  publisher    = {Wiley-Blackwell},
  series       = {ChemMedChem},
  title        = {Structure and Energetics of Ligand–Fluorine Interactions with Galectin-3 Backbone and Side-Chain Amides : Insight into Solvation Effects and Multipolar Interactions},
  url          = {http://dx.doi.org/10.1002/cmdc.201900293},
  year         = {2019},
}