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

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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.

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Acknowledgments

This study was supported by FONDECYT Grant 1110146.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. University of Chile, Santiago, Chile

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

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  1. Cristian Celis-Barros
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  2. Leslie Saavedra-Rivas
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  3. J. Cristian Salgado
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  4. Bruce K. Cassels
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  5. Gerald Zapata-Torres
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Correspondence to Gerald Zapata-Torres.

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Celis-Barros, C., Saavedra-Rivas, L., Salgado, J.C. et al. Molecular dynamics simulation of halogen bonding mimics experimental data for cathepsin L inhibition. J Comput Aided Mol Des 29, 37–46 (2015). https://doi.org/10.1007/s10822-014-9802-7

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  • DOI: https://doi.org/10.1007/s10822-014-9802-7

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