In Silico Development of PABA-substituted Pyrimidine Derivatives Targeting Mutant p53 for Precision Therapy in Oral Squamous Cell Carcinoma

Background: Oral squamous cell carcinoma (OSCC) is a prevalent malignancy with poor prognosis, largely attributed to p53 mutations in 65%–85% of cases. Mutant p53 loses tumour-suppressor functions and gains oncogenic roles, promoting cancer progression and therapy resistance. Targeting mutant p53 represents a promising therapeutic avenue. Aim: The aim of this study was to evaluate the potential of 4-amino benzoic acid (PABA)-substituted pyrimidine derivatives as novel inhibitors of mutant p53 protein through in silico analyses. Materials and Methods: Mutant p53 (PDB ID: 4mzi) was retrieved from the RCSB Protein Data Bank. PABA derivatives (3A, 3B, 3C and 3D) were assessed for drug-likeness, toxicity and binding affinities using Lipinski’s Rule, PROTox-II and AutoDock 4.2. Binding energies, hydrogen bonds and Van der Waals interactions were analysed. Results: All derivatives satisfied Lipinski’s Rule with no violations, demonstrating drug-likeness. Toxicity analysis classified the compounds as non-carcinogenic and non-mutagenic. Binding affinities were highest for 3D (−8.8 kcal/mol) with strong interactions at PRO A: 219, GLY A: 199 and ASN A: 200, forming four hydrogen bonds. Compound 3C (−7.9 kcal/mol) also exhibited significant binding. PABA’s anti-cancer properties and stable protein–ligand interactions highlight its therapeutic potential. Conclusion: PABA-substituted pyrimidine derivatives, particularly 3D, show promise as lead compounds for targeting mutant p53 in OSCC. Further in vitro and in vivo studies are warranted to validate their efficacy and safety, paving the way for precision therapies.