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Published on: February 9, 2021
Computational-based drug design of novel small molecules targeting p53-MDMX interaction
Abel Ujaigbe Egbemhenghe1, Olajide Enoch Aderemi2, Bamidele Samson Omotara2
1Department of Chemistry and Biochemistry, Texas Technology University, Lubbock, TX, USA.
Abstract:
The regulation of the p53 tumor suppressor pathway is critically dependent on the activity of Murine Double Minute 2 (MDM2) and Murine Double Minute X (MDMX) proteins. In certain types of cancer cells, excessive amount of MDMX can poly-ubiquitinate p53, which can result in its degradation, leading to a subsequent reduction in the levels of this protein. Therefore, the design of small-molecule inhibitors targeting the MDMX-p53 interaction has emerged as a promising strategy for cancer therapy. In this study, we employed computational techniques including pharmacophore modeling and molecular docking to identify three potential small molecule inhibitors (CID_25094615, CID_137634453, and CID_25094344) of the MDMX-p53 interaction from a PubChem database. Molecular dynamics of 100000 ps were conducted to assess the stability of the MDMX-inhibitor complexes. Our results showed that all three compounds exhibit stable binding with MDMX, with significantly lower root mean square deviation (RMSD) and fluctuation (RMSF) values than the control ligand, indicating superior stability. Additionally, the three compounds exhibit stronger intermolecular hydrogen bond (HBOND) interactions compared to the control, suggesting stronger stability. Overall, our findings highlight the potential of these compounds as lead candidates for the development of novel anticancer agents that target the MDMX-p53 interaction.Communicated by Ramaswamy H. Sarma.
Insights
Computational methods identified three small molecules that inhibit the MDMX-p53 interaction. These compounds show stable binding and strong hydrogen bonds, offering potential as new anticancer agents targeting the p53 tumor suppressor pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Pharmacology
Background:
- The p53 tumor suppressor pathway is crucial for preventing cancer.
- Dysregulation of MDM2 (Murine Double Minute 2) and MDMX (Murine Double Minute X) proteins impacts p53 stability.
- MDMX overexpression can lead to p53 degradation, promoting cancer development.
Purpose of the Study:
- To identify novel small-molecule inhibitors of the MDMX-p53 interaction.
- To evaluate the binding stability and interactions of potential inhibitors with MDMX.
Main Methods:
- Utilized pharmacophore modeling and molecular docking to screen a PubChem database.
- Performed 100,000 ps molecular dynamics simulations.
- Assessed binding stability using root mean square deviation (RMSD) and root mean square fluctuation (RMSF).
- Analyzed intermolecular hydrogen bond (HBOND) interactions.
Main Results:
- Identified three potential MDMX-p53 inhibitors: CID_25094615, CID_137634453, and CID_25094344.
- All identified compounds demonstrated stable binding to MDMX.
- Compounds exhibited lower RMSD and RMSF values compared to a control ligand, indicating superior stability.
- Stronger intermolecular HBOND interactions were observed for the candidate inhibitors.
Conclusions:
- The identified compounds are promising lead candidates for anticancer drug development.
- Targeting the MDMX-p53 interaction offers a viable therapeutic strategy for cancers with MDMX overexpression.
- These inhibitors show potential for stabilizing p53 and restoring its tumor-suppressive functions.
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