Please use this identifier to cite or link to this item:
|Title:||On the origin of the stereoselective affinity of Nutlin-3 geometrical isomers for the MDM2 protein|
|Keywords:||Brownian dynamics simulation|
Kinetics-based drug discovery
|Citation:||ElSawy, K.M., Verma, C.S., Lane, D.P., Caves, L.S.D. (2013-12-15). On the origin of the stereoselective affinity of Nutlin-3 geometrical isomers for the MDM2 protein. Cell Cycle 12 (24) : 3727-3735. ScholarBank@NUS Repository. https://doi.org/10.4161/cc.27273|
|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 away from the binding site. On the other hand, the trans-Nutlin-3a diastereoisomer exhibits a shorter residence time in the vicinity of MDM2 compared with Nutlin-3a due to destabilization of its encounter complex by the collective interaction of pairs of charged residues on either side of the binding site: Glu25 and Lys51 on one side, and Lys94 and Arg97 on the other side. This destabilization is largely due to the electrostatic potential of the trans-Nutlin-3a isomer being largely positive over extended continuous regions around its structure, which are otherwise well-identified into positive and negative regions in the case of the Nutlin-3a isomer. Such rich insight into the binding processes underlying biological selectivity complements the static view derived from the traditional thermodynamic analysis of the final bound complex. This approach, based on an explicit consideration of the dynamics of molecular association, suggests new avenues for kinetics-based anticancer drug development and discovery. © 2013 Landes Bioscience.|
|Source Title:||Cell Cycle|
|Appears in Collections:||Staff Publications|
Show full item record
Files in This Item:
There are no files associated with this item.
checked on Dec 10, 2018
WEB OF SCIENCETM
checked on Dec 10, 2018
checked on Oct 26, 2018
Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.