Targeting p53-MDM2 pathway with novel triazole-oxazole hybrids: a fragment-based drug discovery approach for next-generation cancer therapies.

Abstract

The tumor suppressor protein p53 plays a pivotal role in regulating key cellular processes, including cell cycle arrest, apoptosis, and DNA repair. Its negative regulator, MDM2, binds to the N-terminal domain of p53 and promotes its degradation, leading to the function inactivation of p53 in many cancers. Disrupting the p53-MDM2 interaction is thus an attractive therapeutic strategy, especially in tumors retaining wild-type p53. In this study, we applied a comprehensive in silico approach combining Fragment-Based Drug Discovery (FBDD), molecular docking, R-group enumeration, MM-GBSA binding energy estimation, ADMET prediction, MD simulations, DFT analysis to identify the novel p53-MDM2 inhibitors. Key findings demonstrated that the designed triazole-oxazole hybrids exhibited stable binding with critical MDM2 residues, improved solubility-driven pharmacokinetic behavior, and favorable electronic properties compared with reference inhibitor. Importantly, solubility-guided fragment design not only improved hit quality but also provided scaffolds with strong therapeutic potential. Overall, this study highlights triazole-oxazole hybrids as promising candidates for p53 reactivation and establishes a rational basis for their further biological evaluation in anticancer therapy.