title: Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition.
abstract: 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 IC50 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.
authors.affiliation: University of Chile, Santiago, Chile.
authors.forename: Cristian
authors.initials: C
authors.lastname: Celis-Barros
authors.forename: Leslie
authors.initials: L
authors.lastname: Saavedra-Rivas
authors.forename: J Cristian
authors.initials: JC
authors.lastname: Salgado
authors.forename: Bruce K
authors.initials: BK
authors.lastname: Cassels
authors.forename: Gerald
authors.initials: G
authors.lastname: Zapata-Torres
mesh_terms: D056668:Cathepsin L / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism; D006219:Halogens / Q000737:chemistry*; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D010100:Oxygen / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D015853:Cysteine Proteinase Inhibitors; D006219:Halogens; D008024:Ligands; D056668:Cathepsin L; D010100:Oxygen