Journal of Computer-Aided Molecular Design

, Volume 29, Issue 1, pp 37–46 | Cite as

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

  • Cristian Celis-Barros
  • Leslie Saavedra-Rivas
  • J. Cristian Salgado
  • Bruce K. Cassels
  • Gerald Zapata-TorresEmail author


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.


Halogen bonding MD simulation Halogenated inhibitors Cathepsin L Interactions 



This study was supported by FONDECYT Grant 1110146.

Conflict of interest

The authors declare no competing financial interests.

Supplementary material

10822_2014_9802_MOESM1_ESM.doc (35.1 mb)
Supplementary material 1 (DOC 35971 kb)


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Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  • Cristian Celis-Barros
    • 1
  • Leslie Saavedra-Rivas
    • 1
  • J. Cristian Salgado
    • 1
  • Bruce K. Cassels
    • 1
  • Gerald Zapata-Torres
    • 1
    Email author
  1. 1.University of ChileSantiagoChile

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