TY - JOUR
T1 - Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition
AU - Celis-Barros, Cristian
AU - Saavedra-Rivas, Leslie
AU - Salgado, J. Cristian
AU - Cassels, Bruce K.
AU - Zapata-Torres, Gerald
N1 - Publisher Copyright:
© 2014 Springer International Publishing Switzerland.
PY - 2015/1
Y1 - 2015/1
N2 - 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.
AB - 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.
KW - Cathepsin L
KW - Halogen bonding
KW - Halogenated inhibitors
KW - Interactions
KW - MD simulation
UR - http://www.scopus.com/inward/record.url?scp=84922089244&partnerID=8YFLogxK
U2 - 10.1007/s10822-014-9802-7
DO - 10.1007/s10822-014-9802-7
M3 - Article
C2 - 25338130
AN - SCOPUS:84922089244
SN - 0920-654X
VL - 29
SP - 37
EP - 46
JO - Journal of Computer-Aided Molecular Design
JF - Journal of Computer-Aided Molecular Design
IS - 1
ER -