Synergistic suppression of cell growth: Phenmiazine derivatives targeting p53 and MDM2 unveiled through hybrid...

Area of Science:

• Oncology
• Medicinal Chemistry
• Computational Biology

Background:

• Lung cancer remains a leading cause of cancer mortality globally.
• Genetic and epigenetic alterations drive cancer cell proliferation.
• Targeting critical proteins like p53 and MDM2 is a key strategy in cancer therapy.

Purpose of the Study:

• To design and synthesize novel phenmiazine derivatives as potential inhibitors of p53 and MDM2 proteins.
• To evaluate the binding affinity and stability of designed molecules using computational methods.
• To identify promising lead compounds for the development of new lung cancer therapeutics.

Main Methods:

• Functional group-based drug design was employed to create phenmiazine ring leads.
• Molecular docking simulations (glide dock) were performed to assess binding to p53 (7A1W) and MDM2 (7AU9) proteins.
• Molecular Mechanics Generalized Born Surface Area (MMGBSA) was used to calculate binding energies.
• Molecular Dynamics (MD) simulations and Density Functional Tight Binding (DFTB) studies were conducted to confirm stability and chemical properties.

Main Results:

• One hundred phenmiazine molecules were designed and docked.
• The best binding energy achieved was -8.16 kcal/mol for an aminobenzoic acid substituted molecule.
• MD simulations confirmed the stability of the complex, with key interactions involving 9 amino acids (hydrophobic and hydrogen bonds).
• DFTB analysis indicated significant molecular stability with an energy gap of 0.0508.

Conclusions:

• Phenmiazine ring derivatives demonstrate potent inhibitory activity against p53 and MDM2.
• The designed aminobenzoic acid substituted phenmiazine derivative shows excellent binding affinity and stability.
• These findings suggest that phenmiazine derivatives are promising lead compounds for eradicating lung cancer.