Identification of new inhibitors of Mdm2–p53 interaction via pharmacophore and structure-based virtual screening
Received 3 August 2018
Accepted for publication 3 October 2018
Published 2 November 2018 Volume 2018:12 Pages 3741—3752
Checked for plagiarism Yes
Review by Single-blind
Peer reviewer comments 3
Editor who approved publication: Dr Anastasios Lymperopoulos
Noor Atatreh,1 Mohammad A Ghattas,1 Sanaa K Bardaweel,2 Sara Al Rawashdeh,1 Mohammad Al Sorkhy1
1Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University of Science and Technology, Al Ain, Abu Dhabi, United Arab Emirates; 2Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman 11942, Jordan
Background: The tumor suppressor protein p53 plays an important role in preventing tumor formation and progression through its involvement in cell division control and initiation of apoptosis. Mdm2 protein controls the activity of p53 protein through working as ubiquitin E3 ligase promoting p53 degradation through the proteasome degradation pathway. Inhibitors for Mdm2-p53 interaction have restored the activity of p53 protein and induced cancer fighting properties in the cell.
Purpose: The objective of this study is to use computer-aided drug discovery techniques to search for new Mdm2-p53 interaction inhibitors.
Methods: A set of pharmacophoric features were created based on a standard Mdm2 inhibitor and this was used to screen a commercial drug-like ligand library; then potential inhibitors were docked and ranked in a multi-step protocol using GLIDE. Top ranked ligands from docking were evaluated for their inhibition activity of Mdm2-p53 interaction using ELISA testing.
Results: Several compounds showed inhibition activity at the submicromolar level, which is comparable to the standard inhibitor Nutlin-3a. Furthermore, the discovered inhibitors were evaluated for their anticancer activities against different breast cancer cell lines, and they showed an interesting inhibition pattern.
Conclusion: The reported inhibitors can represent a starting point for further SAR studies in the future and can help in the discovery of new anticancer agents.
Keywords: protein–protein interaction, virtual screening, Mdm2, p53, anticancer, docking, pharmacophore, ELISA
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