Identification of a 1, 8-naphthyridine-containing compound endowed with the inhibition of p53-MDM2/X interaction signaling: a computational perspective

• Published in: Molecular diversity 2024-06, Vol.28 (3), p.1109-1127
• Main Authors: Olukunle, Oluwatoyin Folake, Olowosoke, Christopher Busayo, Khalid, Aqsa, Oke, Grace Ayomide, Omoboyede, Victor, Umar, Haruna Isiyaku, Ibrahim, Ochapa, Adeboboye, Covenant Femi, Iwaloye, Opeyemi, Olawale, Femi, Adedeji, Ayodeji Adeola, Bello, Taye, Alabere, Hafsat Olateju, Chukwuemeka, Prosper Obed
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Biochemistry; Biomedical and Life Sciences; Cancer therapies; Cell cycle; Drug resistance; Genes; Geometry; Humans; Life Sciences; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Naphthyridines - chemistry; Naphthyridines - pharmacology; Optimization techniques; Organic Chemistry; Original Article; Pharmacy; Polymer Sciences; Protein Binding; Proteins; Proto-Oncogene Proteins c-mdm2 - antagonists & inhibitors; Proto-Oncogene Proteins c-mdm2 - chemistry; Proto-Oncogene Proteins c-mdm2 - metabolism; Signal Transduction - drug effects; Software; Tumor Suppressor Protein p53 - antagonists & inhibitors; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1381-1991; 1573-501X; 1573-501X
• DOI: 10.1007/s11030-023-10637-3

Various studies have established that molecules specific for MDMX inhibition or optimized for dual inhibition of p53-MDM2/MDMX interaction signaling are more suitable for activating the Tp53 gene in tumor cells. Nevertheless, there are sparse numbers of approved molecules to treat the health consequences brought by the lost p53 functions in tumor cells. Consequently, this study explored the potential of a small molecule ligand containing 1, 8-naphthyridine scaffold to act as a dual inhibitor of p53-MDM2/X interactions using computational methods. The results obtained from quantum mechanical calculations revealed our studied compound entitled CPO is more stable but less reactive compared to standard dual inhibitor RO2443. Like RO2443, CPO also exhibited good non-linear optical properties. The results of molecular docking studies predicted that CPO has a higher potential to inhibit MDM2/MDMX than RO2443. Furthermore, CPO was stable over 50 ns molecular dynamics (MD) simulation in complex with MDM2 and MDMX respectively. On the whole, CPO also exhibited good drug-likeness and pharmacokinetics properties compared to RO2443 and was found with more anti-cancer activity than RO2443 in bioactivity prediction. CPO is anticipated to elevate effectiveness and alleviate drug resistance in cancer therapy. Ultimately, our results provide an insight into the mechanism that underlay the inhibition of p53-MDM2/X interactions by a molecule containing 1, 8-naphthyridine scaffold in its molecular structure. Graphical abstract