On the origin of the stereoselective affinity of Nutlin-3 geometrical isomers for the MDM2 protein.

ABSTRACT: The stereoselective affinity of small-molecule binding to proteins is typically broadly explained in terms of the thermodynamics of the final bound complex. Using Brownian dynamics simulations, we show that the preferential binding of the MDM2 protein to the geometrical isomers of Nutlin-3, an effective anticancer lead that works by inhibiting the interaction between the proteins p53 and MDM2, can be explained by kinetic arguments related to the formation of the MDM2:Nutlin-3 encounter complex. This is a diffusively bound state that forms prior to the final bound complex. We find that the MDM2 protein stereoselectivity for the Nutlin-3a enantiomer stems largely from the destabilization of the encounter complex of its mirror image enantiomer Nutlin-3b, by the K70 residue that is located awa

SUBMITTER: ElSawy KM 

PROVIDER: S-EPMC3905064 | biostudies-literature | 2013 Dec

REPOSITORIES: biostudies-literature