Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition.

Celis-Barros, Cristian; Saavedra-Rivas, Leslie; Salgado, J.; Cassels, Bruce; Zapata-Torres, Gerald

A MD simulation protocol was developed to model halogen bonding in protein-ligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. This protocol was then used to simulate the interactions of cathepsin L with a series of halogenated and non-halogenated inhibitors. Our results show that chloro, bromo and iodo derivatives have progressively narrower distributions of calculated geometries, which reflects the order of affinity I > Br > Cl, in agreement with the IC values. Graphs for the Cl, Br and I analogs show stable interactions between the halogen atom and the Gly61 carbonyl oxygen of the enzyme. The halogen-oxygen distance is close to or less than the sum of the van der Waals radii; the C-X···O angle is about 170°; and the X···O=C angle approaches 120°, as expected for halogen bond formation. In the case of the iodo-substituted analogs, these effects are enhanced by introduction of a fluorine atom on the inhibitors' halogen-bonding phenyl ring, indicating that the electron withdrawing group enlarges the σ-hole, resulting in improved halogen bonding properties.

MOLECULAR dynamics; CATHEPSINS; SIMULATION methods & models; PROTEIN-ligand interactions; GRAPHIC methods

Journal of Computer-Aided Molecular Design, 2015, Vol 29, Issue 1, p37

0920-654X

Academic Journal

10.1007/s10822-014-9802-7