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How and when does an anticancer drug leave its binding site?

Pratyush Tiwary1, Jagannath Mondal2, B J Berne1

  • 1Department of Chemistry, Columbia University, New York, NY 10027, USA.

Science Advances
|June 6, 2017
PubMed

Insights

Researchers simulated the anticancer drug dasatinib unbinding from c-Src kinase. Water molecules facilitate unbinding by acting as a molecular switch, explaining challenges in developing drugs with longer residence times.

Area of Science:

  • Biochemistry
  • Computational Biology
  • Pharmacology

Background:

  • Atomistic resolution of drug unbinding from proteins is a significant experimental and computational challenge.
  • Understanding drug-protein interactions is crucial for developing effective therapeutics.

Purpose of the Study:

  • To elucidate the atomistic mechanisms of dasatinib unbinding from c-Src kinase.
  • To investigate the role of protein-water interactions in drug residence time.

Main Methods:

  • Enhanced sampling molecular dynamics simulations were employed.
  • Multiple unbinding trajectories were generated and analyzed.

Main Results:

  • Dasatinib unbinding pathways from c-Src kinase were resolved at atomistic detail.
  • Simulated residence time agreed with experimental data.
  • Coupled protein-water movements and metastable intermediates were observed.
  • Water molecules were found to form a hydrogen bond bridge, elongating a salt bridge and facilitating conformational changes essential for unbinding.

Conclusions:

  • Water insertion into the salt bridge acts as a critical molecular switch controlling dasatinib unbinding.
  • The findings provide a mechanistic explanation for difficulties in engineering drugs with prolonged residence times against specific kinase conformations.
Keywords:
conformation selectiondrug unbindingkinasemolecular dynamicswater

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