Halogen Bonds in Biological Context

LUCHI, ADRIANO MARTIN; ANGELINA, EMILIO L.; ANDUJAR, SEBASTIAN A.; ENRIZ, RICARDO DANIEL; PERUCHENA, NÉLIDA M.

Carlos Paz

Conferencia; 13th Latin American Conference on Physical Organic Chemistry; 2015

INFIQC-CONICET

Inthis work, Halogen Bond (XB) interactions formed by halogenatedligands (LX, with X = Cl, Br, I) at the Dopamine Receptor D2 (DRD2)binding pocket, were studied by Molecular Dynamics (MD) Docking andcharge density analysis. The strength and nature of these XBs werecontrasted with the Hydrogen Bond (HB) interactions established bynon-halogenated analogs (LOH and LH, where X was replaced by OH andH, respectively).Theligands for this study were extracted from a dataset of compoundsdeposited in ZINC database that were active in direct binding assaysto DRD2 (~3.7K compounds). This dataset was subjected to thefiltering rules in the scheme below in order to find thehalogenated/non-halogenated pairs that were then submitted to MDsimulations. A homology model of DRD2 [1] was employed for thesimulations since no crystal structure is yet available for thereceptor. To mimic the positive cap (sigma hole) on the halogen atom, amassless, positive charged extra point (EP) was introduced in theforce field during the MD simulations [2]. Binding free energies werecomputed from DM trajectories for halogenated/non-halogenated pairsand contrasted with the experimental binding affinity data tovalidate the modeling. Finally, a topological analysis of the chargedensity based on QTAIM theory [3] was performed on reduced models ofboth halogenated and non-halogenated ligand-receptor complexes inorder to explain their binding affinity differences in terms of thenetwork of non-covalent interactions established in each case, in thereceptor binding pocket.Whilea lot of ligands for DRD2 have been reported from binding andfunctional assays, there is scarce structural evidence on how theseligands actually binds to the receptor because crystallization ofG-Protein Coupled Receptors (GPCRs) is very challenging. Accordingly,our structural approach based in a homology model of DRD2 was able todescribe the key interactions that stabilize the ligand-DRD2complexes, giving at the same time some clues on how to improve themby halogen bonding. Hopefully, this information will be useful forthe design of novel compounds targeting DRD2.[1]M. A. Soriano-Ursúa, J. O. Ocampo-López, K. Ocampo-Mendoza, J. G.Trujillo-Ferrara, J. Correa-Basurto, Comput. Biol.Med. 2011, 41, 537?445. [2] M. A. A. Ibrahim, J. Comput. Chem.2011, 32, 2564-2574. [3] R. W. Bader, Atoms in Molecules: A QuantumTheory, Oxford University Press, New York, 1990