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

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Science Advances  31 May 2017:
Vol. 3, no. 5, e1700014
DOI: 10.1126/sciadv.1700014

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Obtaining atomistic resolution of drug unbinding from a protein is a much sought-after experimental and computational challenge. We report the unbinding dynamics of the anticancer drug dasatinib from c-Src kinase in full atomistic resolution using enhanced sampling molecular dynamics simulations. We obtain multiple unbinding trajectories and determine a residence time in agreement with experiments. We observe coupled protein-water movement through multiple metastable intermediates. The water molecules form a hydrogen bond bridge, elongating a specific, evolutionarily preserved salt bridge and enabling conformation changes essential to ligand unbinding. This water insertion in the salt bridge acts as a molecular switch that controls unbinding. Our findings provide a mechanistic rationale for why it might be difficult to engineer drugs targeting certain specific c-Src kinase conformations to have longer residence times.

  • drug unbinding
  • kinase
  • molecular dynamics
  • water
  • conformation selection

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