Structure-based designing efficient peptides based on p53 binding site residues to disrupt p53-MDM2/X interaction

• Published in: Scientific reports Vol. 10; no. 1; p. 11449
• Main Authors: Rasafar, Nasim, Barzegar, Abolfazl, Mehdizadeh Aghdam, Elnaz
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 10.07.2020; Nature Publishing Group
• Subjects: 631/114/2397; 631/67/1059/153; Amino Acid Sequence - genetics; Binding sites; Binding Sites - genetics; Cell Cycle Proteins - genetics; Computational Biology; Humanities and Social Sciences; Humans; MDM2 protein; Molecular Dynamics Simulation; multidisciplinary; Mutants; Neoplasms - drug therapy; Neoplasms - genetics; Original Research; p53 Protein; Peptides; Peptides - chemistry; Peptides - genetics; Protein Binding - genetics; Protein Conformation - drug effects; Protein structure; Protein Structure, Secondary - drug effects; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins c-mdm2 - genetics; Sampling; Science; Science (multidisciplinary); Secondary structure; Tumor Suppressor Protein p53 - genetics
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-67510-8

MDM2 and MDMX are known as overexpressed oncoproteins in several wild-type p53 cancer cells. The development of potent and dual antagonist peptides for p53-MDM2/X is a continuous challenge. In this study, we intended to investigate the pivotal structural points respecting the development of potent and dual inhibitors of MDM2/X. Correspondingly, MD simulation was performed on the experimentally confirmed peptides, comprising p53, pDI, pDIQ, PMI, and computationally screened mutant pDI and pDIQ. A follow-up secondary structure analysis showed the last three C-terminal residues provide the helicity reservation of peptides bound to MDM2/X. Furthermore, a delicate residue-residue examination displayed Met 11 and Ser12 in the modified peptides contribute significantly to dual inhibition of MDM2/X. Additionally, the peptides_MDM2/X complexes’ ΔG binding extracted by the umbrella sampling method were in agreement with the pattern of their experimental affinity values. It was concluded the screened pDI mutants were considered as suitable anti-MDM2/X peptides, and the data obtained could be exploited as the theoretical structure-based guide for rational peptide design. Taking account of results, the suitable C-terminal residues of p53-based peptides especially Met11, and Ser12, as well as higher umbrella sampling, generated ΔG binding to MDM2/X would be considered as the positive structural markers of a promising anti-cancer agent.