Aceclofenac and interactions analysis in the crystal and COX protein active site

Abstract An experimental charge density analysis of the anti-inflammatory drug aceclofenac has been accomplished and compared with periodic Density Functional results. Diffraction data sets were measured on two crystals on a Bruker Photon II detector. The merging of the two data sets resulted in improved crystallographic R-factors. The analysis of the intermolecular contact types and their enrichments highlights the driving forces of the crystal packing. Strong hydrogen bonds C=O…H–O between carboxylic groups act as one of the main backbones in the crystal packing while halogen bonding Cl…O and the non-polar contacts C–H…Cl are also well represented. The C6H4Cl2N heterocycle forms aromatic donor–acceptor parallel self-interactions through an inversion center while the less substituted C6CH4N cycle is more involved in C–H…π interactions. The N atom linking the two phenyl rings presents mixed sp2/sp3 hybridization and bears a weak but visible electron lone pair. The electrostatic potentials generated by the molecule and by its surrounding on the Hirshfeld surface were analyzed and show a good electrostatic complementarity for the charged regions of the molecule, while the non-polar regions interact with each other. The electrostatic energies computed between interacting dimers in the crystal show that the strongest dimer is the one forming two O–H...O hydrogen bonds. The electron density ellipticity and Laplacian values were analyzed on the covalent bonds critical points. The C–H bonds on the two aromatic C6 rings have a modest but significant ellipticity value  = 0.048, presumably due to the proximity of the C–C bonds with π character of the carbon atoms involved in the bonds. Theoretical geometry optimizations performed on the isolated molecule and on crystallographic dimers show the effect of the intermolecular interactions on the molecular conformation, which is slightly affected by the crystal packing. The aceclofenac medicinal compound, metabolized into diclofenac after loss of an acetic acid group, binds in vivo to the target COX-2 protein. An electron density model of diclofenac has been derived from the refined electron density of aceclofenac. The interactions between diclofenac and the protein were analyzed from an electrostatic and Hirshfeld surface analysis points of views.