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

Pratyush Tiwary; Jagannath Mondal; Bruce J. Berne

Title:
How and when does an anticancer drug leave its binding site?
Author(s):
Tiwary, Pratyush
Mondal, Jagannath
Berne, Bruce J.
Date:
Type:
Articles
Department(s):
Chemistry
Volume:
3
Persistent URL:
Book/Journal Title:
Science Advances
Abstract:
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.
Subject(s):
Biochemistry
Molecular dynamics
Antineoplastic agents
Drugs
Chemical engineering
Binding sites (Biochemistry)
Publisher DOI:
https://doi.org/10.1126/sciadv.1700014
Item views
20
Metadata:
text | xml
Suggested Citation:
Pratyush Tiwary, Jagannath Mondal, Bruce J. Berne, , How and when does an anticancer drug leave its binding site?, Columbia University Academic Commons, .

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