Jump to main content
Jump to site search
Access to RSC content Close the message box

Continue to access RSC content when you are not at your institution. Follow our step-by-step guide.

Is breaking of a hydrogen bond enough to lead to drug resistance?

Author affiliations


Drug resistance is a serious problem in cancer, viral, bacterial, fungal and parasitic diseases. Examination of crystal structures of protein–drug complexes is often not enough to explain why a certain mutation leads to drug resistance. As an example, the crystal structure of the kinase inhibitor dasatinib bound to the Abl1 kinase shows a hydrogen bond between the drug and residue Thr315 and very few contacts between the drug and residues Val299 and Phe317, yet mutations in those residues lead to drug resistance. In the first case, it is tempting to suggest that the loss of a hydrogen bond leads to drug resistance, whereas in the other two cases it is not known why mutations lead to drug resistance in the first place. We carried out extensive molecular dynamics (MD) simulations and free energy calculations to explain drug resistance to dasatinib from a molecular point of view and show that resistance is due to a multitude of subtle effects. Importantly, our calculations could reproduce the experimental values for the binding energies upon mutations in all three cases and shed light on their origin.

Graphical abstract: Is breaking of a hydrogen bond enough to lead to drug resistance?

Back to tab navigation

Supplementary files

Article information

24 Mar 2020
06 May 2020
First published
07 May 2020

Chem. Commun., 2020, Advance Article
Article type

Is breaking of a hydrogen bond enough to lead to drug resistance?

M. J. Dávila-Rodríguez, T. S. Freire, E. Lindahl, I. Caracelli, J. Zukerman-Schpector and R. Friedman, Chem. Commun., 2020, Advance Article , DOI: 10.1039/D0CC02164D

Social activity

Search articles by author