Publication: Ensemble-based virtual screening reveals dual-inhibitors for the p53-MDM2/MDMX interactions
All || By Area || By Year| Title | Ensemble-based virtual screening reveals dual-inhibitors for the p53-MDM2/MDMX interactions | Authors/Editors* | K. Barakat, J. Mane, D. Friesen, J. Tuszynski |
|---|---|
| Where published* | Journal of Molecular Graphics and Modelling |
| How published* | Journal |
| Year* | 2010 |
| Volume | 28 |
| Number | 6 |
| Pages | 556-568 |
| Publisher | |
| Keywords | |
| Link | |
| Abstract |
The p53 protein, a guardian of the genome, is inactivated by mutations or deletions in approximately half of human tumors. While in the rest of human tumors, p53 is expressed in wild-type form, yet it is inhibited by over-expression of its cellular regulators MDM2 and MDMX proteins. Although the p53-binding sites within the MDMX and MDM2 proteins are closely related, known MDM2 small-molecule inhibitors have been shown experimentally not to bind to its homolog, MDMX. As a result, the activity of these inhibitors including Nutlin3 is compromised in tumor cells over-expressing MDMX, preventing these compounds from fully activating the p53 protein. Here, we applied the relaxed complex scheme (RCS) to allow for the full receptor flexibility in screening for dual-inhibitors that can mutually antagonize the two p53-regulator proteins. First, we filtered the NCI diversity set, DrugBank compounds and a derivative library for MDM2-inhibitors against 28 dominant MDM2-conformations. Then, we screened the MDM2 top hits against the binding site of p53 within the MDMX target. Results described herein identify a set of compounds that have been computationally predicted to ultimately activate the p53 pathway in tumor cells retaining the wild-type protein. |
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