Halogen Bonds in biological context

M.A.LUCHI; E. ANGELINA; S. ANDUJAR; ENRIZ R D; N. PERUCHENA

Carlos paz

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

In this work, Halogen Bond (XB) interactions formed by halogenated ligands (LX, with X = Cl, Br, I)at the Dopamine Receptor D2 (DRD2) binding pocket, were studied by Molecular Dynamics (MD)Docking and charge density analysis. The strength and nature of these XBs were contrasted withthe Hydrogen Bond (HB) interactions established by non-halogenated analogs (LOH and LH, whereX was replaced by OH and H, respectively).The ligands for this study were extracted from a dataset of compounds deposited in ZINC databasethat were active in direct binding assays to DRD2 (~3.7K compounds). This dataset was subjectedto the filtering rules in the scheme below in order to find the halogenated/non-halogenated pairs thatwere then submitted to MD simulations. A homology model of DRD2 [1] was employed for thesimulations since no crystal structure is yet available for the receptor. To mimic the positive cap (σ-hole) on the halogen atom, a massless, positive charged extra point (EP) was introduced in theforce field during the MD simulations [2]. Binding free energies were computed from DM trajectoriesfor halogenated/non-halogenated pairs and contrasted with the experimental binding affinity data tovalidate the modeling. Finally, a topological analysis of the charge density based on QTAIM theory[3] was performed on reduced models of both halogenated and non-halogenated ligand-receptorcomplexes in order to explain their binding affinity differences in terms of the network of noncovalentinteractions established in each case, in the receptor binding pocket.While a lot of ligands for DRD2 have been reported from binding and functional assays, there isscarce structural evidence on how these ligands actually binds to the receptor becausecrystallization of G-Protein Coupled Receptors (GPCRs) is very challenging. Accordingly, ourstructural approach based in a homology model of DRD2 was able to describe the key interactionsthat stabilize the ligand-DRD2 complexes, giving at the same time some clues on how to improvethem by halogen bonding. Hopefully, this information will be useful for the design of novelcompounds targeting DRD2.