1 research outputs found
Benzene Probes in Molecular Dynamics Simulations Reveal Novel Binding Sites for Ligand Design
Protein
flexibility poses a major challenge in binding site identification.
Several computational pocket detection methods that utilize small-molecule
probes in molecular dynamics (MD) simulations have been developed
to address this issue. Although they have proven hugely successful
at reproducing experimental structural data, their ability to predict
new binding sites that are yet to be identified and characterized
has not been demonstrated. Here, we report the use of benzenes as
probe molecules in ligand-mapping MD (LMMD) simulations to predict
the existence of two novel binding sites on the surface of the oncoprotein
MDM2. One of them was serendipitously confirmed by biophysical assays
and X-ray crystallography to be important for the binding of a new
family of hydrocarbon stapled peptides that were specifically designed
to target the other putative site. These results highlight the predictive
power of LMMD and suggest that predictions derived from LMMD simulations
can serve as a reliable basis for the identification of novel ligand
binding sites in structure-based drug design