title: Charge density and electrostatic interactions of fidarestat, an inhibitor of human aldose reductase.
abstract: 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 modeled electron density was used to calculate the electrostatic interaction energy of fidarestat and its (2R,4S) stereoisomer with the human aldose reductase 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 pi system as an acceptor. All the chemical bonds and the intermolecular interactions, especially these two pi...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 (2R,4S) stereoisomer with human aldose reductase were modeled with a multipolar atom model transferred from our experimental 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.
authors: Laboratoire de Cristallographie, Résonance Magnétique et Modélisations (CRM2), CNRS, UMR 7036, Institut Jean Barriol, Faculté des Sciences et Techniques, Nancy Université, BP 70239, 54506 Vandoeuvre-les-Nancy Cedex, France.
authors: Bertrand
authors: B
authors: Fournier
authors: El-Eulmi
authors: el-E
authors: Bendeif
authors: Benoît
authors: B
authors: Guillot
authors: Alberto
authors: A
authors: Podjarny
authors: Claude
authors: C
authors: Lecomte
authors: Christian
authors: C
authors: Jelsch
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D020134:Catalytic Domain; D004791:Enzyme Inhibitors / Q000737:chemistry; D006801:Humans; D006860:Hydrogen Bonding; D048289:Imidazolidines / Q000737:chemistry*; D008958:Models, Molecular; D055672:Static Electricity; D014961:X-Ray Diffraction
chemical_list: D004791:Enzyme Inhibitors; D048289:Imidazolidines; C077139:fidarestat; D000449:Aldehyde Reductase