Ensemble-based virtual screening reveals dual-inhibitors for the p53-MDM2/MDMX interactions
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Published on: March 28, 2021
Khaled Barakat1, Jonathan Mane, Douglas Friesen
1Department of Physics, University of Alberta, Edmonton, AB, Canada.
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.
Insights
Researchers identified novel dual-inhibitors targeting MDM2 and MDMX proteins to reactivate the p53 pathway. These compounds show promise for treating tumors with wild-type p53, offering a new therapeutic strategy against cancer.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The p53 protein, crucial for genome integrity, is often inactivated in human cancers.
- In tumors with wild-type p53, its function is suppressed by overexpressed MDM2 and MDMX proteins.
- Existing MDM2 inhibitors are ineffective against MDMX, limiting their therapeutic potential.
Purpose of the Study:
- To discover novel dual-inhibitors targeting both MDM2 and MDMX proteins.
- To overcome the limitations of current inhibitors in tumors overexpressing MDMX.
- To develop compounds capable of reactivating the p53 pathway in cancer cells.
Main Methods:
- Utilized the relaxed complex scheme (RCS) for flexible receptor modeling in virtual screening.
- Screened compound libraries (NCI diversity set, DrugBank, derivative library) against multiple MDM2 conformations.
- Validated top MDM2 inhibitor candidates against the MDMX binding site.
Main Results:
- Identified a set of compounds predicted to inhibit both MDM2 and MDMX.
- These compounds demonstrated potential for dual antagonism of p53 regulators.
- Computational predictions suggest these inhibitors can activate the p53 pathway.
Conclusions:
- The study presents a computational strategy for identifying dual-inhibitors of MDM2 and MDMX.
- The identified compounds offer a promising avenue for reactivating p53 in wild-type p53 tumors.
- This research could lead to new cancer therapies targeting the p53 pathway.
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