Charge Density and Electrostatic Interactions of Fidarestat, an Inhibitor of Human Aldose Reductase

Bertrand Fournier (1) , El-Eulmi Bendeif (1) , Benoît Guillot (1) , Alberto Podjarny (2) , Claude Lecomte (1) , Christian Jelsch (1)

1 CRM2 - Cristallographie, Résonance Magnétique et Modélisations
2 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

The charge density and the topological features of fidarestat, an inhibitor of human aldose reductase, have been determined from ultra high-resolution X-ray diffraction data at 100 K. The modelled electron density was used to calculate the electrostatic interaction energy of fidarestat and its (2R4S) stereoisomer with the human Aldose Reducase by using the ELMAM database as coded in the MoPro program. Such calculation may be extended to other protein complexes for which accurate high resolution X-ray data are available. The paper also discusses the hydrogen bonds in the fidarestat crystal. There are notably two hydrogen bonds with a π system as acceptor. All the chemical bonds and the intermolecular interactions, especially these two π…H bonds, have been quantitatively studied by topological analysis. The three-dimensional electrostatic potential calculated on the molecular surface emphasizes the preferential polar binding sites of fidarestat. Theses interacting features in the molecule are crucial for drug-receptor recognition. The interactions between chemical groups in the crystal are also analyzed by computing the electrostatic energy using the latest advancements of the MoPro crystallographic software. The complexes of fidarestat and its (2R4S) stereoisomer with human aldose reductase were modelled with a multipolar atom model transferred from our electron density database. Accurate estimation of electrostatic interaction energy between inhibitors and the main residues of the protein active site is derived from this high detail level of the electron density.

Domaines: Cristallographie; Chimie thérapeutique; Médicaments

Bertrand Fournier, El-Eulmi Bendeif, Benoît Guillot, Alberto Podjarny, Claude Lecomte, et al.. Charge Density and Electrostatic Interactions of Fidarestat, an Inhibitor of Human Aldose Reductase. Journal of the American Chemical Society, 2009, 131 (31), pp.10929-10941. ⟨10.1021/ja8095015⟩. ⟨hal-01720074⟩