Computational-based drug design of novel small molecules targeting p53-MDMX interaction.

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.

Identification of EGFR inhibitors as potential agents for cancer therapy: pharmacophore-based modeling, molecular docking, and molecular dynamics investigations.

CONTEXT: As a member of a large family of proteins that together regulate various aspects of cell growth and development, the epidermal growth factor receptor (EGFR) is a validated target for the development of new drugs. Herein, we compiled a library of 62 compounds from the PubChem database with similar pharmacophores as osimertinib, which to our knowledge represents the only drug capable of overcoming EGFR-T790M-mutated NSCLC until date. Subsequently, we launched a docking-based virtual screening campaign against the EGFR kinase with the compiled chemical entities. The virtual screen identified 3 hit candidates (CID_126667097, CID_137660592, and CID_137659061) with lower binding energy/higher affinity (- 8.7 kcal/mol, - 8.6 kcal/mol, and - 8.5 kcal/mol, respectively) than the standard osimertinib (- 8.4 kcal/mol). Molecular dynamics metrics such as RMSD, RMSF, ROG, and intermolecular H-bond were used to substantiate the stability of the promising drug candidates at the binding pocket of EGFR after 100,000 ps production run. Overall, our molecular modeling study portrayed CID_126667097, CID_137660592, and CID_137659061 as lead-like drug candidates that may be further developed for the treatment of EGFR-associated cancer disease. METHODS: Molecular docking was conducted with Autodock Vina. A total of 62 compounds were compiled for the docking screen, which were then downloaded in SMILE format and converted to Protein Data Bank (PDB) format using the Openbabel online server. Finally, Gromacs 2022.3 was used to perform MD simulation to substantiate the stability of the hit candidates.