The role of ETFS amino acids on the stability and inhibition of p53-MDM2 complex of anticancer p53-derivatives peptides: Density functional theory and molecular docking studies.
Soriano-Correa. Catalina C; Vichi-Ramírez. Micheel Merari MM; Herrera-Valencia. Edtson E EE; Barrientos-Salcedo. Carolina C
Key Findings
- The ETFS segment (E17, T18, S20) improves hydrogen‑bonding and overall peptide stability.
- Amino acids F19, W23 and V25 promote an alpha‑helix shape that is important for binding.
- Molecular docking predicts that PNC‑27B, PNC‑28B, PNC‑27 and PNC‑28A have the strongest binding energies to MDM2, potentially blocking the p53‑MDM2 interaction.
Practical Outcomes
- These results point to PNC‑27B, PNC‑28B and PNC‑28A as promising candidates for anti‑cancer peptide development, but they are based only on computer simulations. No dosage, safety, or real‑world efficacy data are provided, so biohackers should view them as early‑stage leads that need laboratory and clinical testing before any self‑experimentation.
Summary
Scientists used computer models to see how tiny protein pieces (peptides) called PNC‑27, PNC‑27B, PNC‑28A and PNC‑28B might block a cancer‑related interaction between the proteins p53 and MDM2. The calculations suggest that certain amino‑acid tweaks (especially adding E, T and S) make the peptides stick better to MDM2 and stay stable, which could help keep the natural tumor‑suppressor p53 active.
Abstract
Cancer is one of the leading causes of mortality in the world. Despite the existence of diverse antineoplastic treatments, these do not possess the expected efficacy in many cases. Knowledge of the molecular mechanisms involved in tumor processes allows the identification of a greater number of therapeutic targets employed in the study of new anticancer drugs. In the last decades, peptide-based therapy design using computational chemistry has gained importance in the field of oncology therapeutics. This work aims to evaluate the electronic structure, physicochemical properties, stability, and inhibition of ETFS amino acids and peptides derived from the p53-MDM2 binding domain with action in cancer cells; by means of chemical descriptors at the DFT-BHandHLYP level in an aqueous solution, and its intermolecular interactions through molecular docking studies. The results show that The ETFS fragment plays a critical role in the intermolecular interactions. Thus, the amino acids E17, T18 and S20 increase intermolecular interactions through hydrogen bonds and enhance structural stability. F19, W23 and V25 enhance the formation of the alpha-helix. The hydrogen bonds formed by the backbone atoms for PNC-27, PNC-27-B and PNC-28 stabilize the α-helices more than hydrogen bonds formed by the side chains atoms. Also, molecular docking indicated that the PNC27B-MDM2, PNC28B-MDM2, PNC27-MDM2 and PNC28A-MDM2 complexes show the best binding energy. Therefore, DFT and molecular docking studies showed that the proposed peptides: PNC-28B, PNC-27B and PNC-28A could inhibit the binding of MDM2 to the p53 protein, decreasing the translocation and degradation of p53 native protein.
Study Information
pubmed
2023
2023-04-13T00:00:00.000Z
10.1016/j.jmgm.2023.108472
7
47