Halogen bonding in biological context: a computational study of D2 dopamine receptor

ADRIANO M. LUCHI; EMILIO L. ANGELINA; SEBASTIÁN A. ANDUJAR; RICARDO D. ENRIZ; NÉLIDA M. PERUCHENA

JOURNAL OF PHYSICAL ORGANIC CHEMISTRY

JOHN WILEY & SONS LTD

Lugar: LOndres; Año: 2016

0894-3230

In this work, Halogen Bond (X-bond) interactions formed by halogenated ligands (LX) at the Dopamine Receptor D2(DRD2) binding pocket were studied by Molecular Dynamics (MD) and charge density analysis. The X-bonds werecontrasted with the Hydrogen Bond (H-bond) interactions established by hydroxylated analogs (LOH, where Xwas replaced by OH). The ligands for this study were extracted from a dataset of compounds deposited in ZINC da-tabase that were active in binding assays to DRD2. This dataset was subjected to the filtering rules by employingcheminformatics tools to find the LX/LOH pairs that were then submitted to MD simulations. A homology modelof DRD2 was employed for the simulations because no crystal structure is yet available for the receptor. To mimicthe positive cap (σ-hole) on the halogen atom, a massless, positive charged extra-point was introduced in the forcefield. An analysis of the charge density (QTAIM) was performed on reduced models of simulated complexes to ex-plain their binding differences. Results show that the halogen atom tends to form X-bond with protein backbone ox-ygen atom. Two out of the four halogenated ligands studied form a specific X-bond with the carbonyl oxygen ofSer193. This specific X-bond decreases the inherent propensity of transmembrane 5 to unfolding. These results sug-gest a possible role of the X-bond as a protein secondary structure modulator because of the ability of the halogento interact with the protein backbone.