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<p>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.</p>

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

  • 期刊论文

  • 发表日期：

    2025年9月23日

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  • Apurva Prajapati,
  • Hitesh Patel

摘要

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.