Artículo de revista
Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition
Date
2015Registration in:
J Comput Aided Mol Des (2015) 29:37–46
1573-4951
DOI: 10.1007/s10822-014-9802-7
Author
Celis Barros, Cristian
Saavedra Rivas, Leslie
Salgado Herrera, José Cristián
Cassels Niven, Bruce
Zapata Torres, Gerald
Institutions
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’ halogenbonding
phenyl ring, indicating that the electron withdrawing
group enlarges the r-hole, resulting in improved
halogen bonding properties.