Résumé
KAT6A is an enzyme that regulates biological processes that are linked to cancer cell proliferation and metastasis. Recent studies suggest that certain compounds from Withania somnifera may inhibit cancer growth by targeting KAT6A. However, the impact of mutations on KAT6A's structure and the inhibitory potential of compounds obtained from W. somnifera remain unclear. This study investigated three mutations, K181N, R242P and R325C, using molecular docking, molecular dynamics simulations and network pharmacology to assess their effects on KAT6A's interaction with its coenzyme, acetyl-CoA (CoA), and inhibitors (WM8014, withasomniferol B, withanolide E and sitoindoside IX). The results showed that R242P and R325C mutations significantly reduced binding affinity (from −12.94 kcal/mol to −9.96 and −7.00 kcal/mol, respectively) and increased RMSD values (from 1.860 to 2.296 and 2.373, respectively) compared to K181N (−11.86 kcal/mol and 1.698), suggesting altered enzyme activity. Notably, these mutations enhanced the inhibitory effects of the compounds from W. somnifera, particularly withanolide E, which showed reduced RMSD values (2.259–2.211, 2.045 and 1.985 for K181N, R242P, and R325C, respectively). Additionally, mutant complexes showed higher binding energies, including R325C-WM8014 (−90.53 kcal/mol), K181N-CoA (−90.50 kcal/mol) and R242P-withanolide E (−82.06 kcal/mol) compared to their corresponding wild-type complexes, which exhibited −85.25 kcal/mol, −69.30 kcal/mol and −57.08 kcal/mol, respectively. Network pharmacology also revealed that the compounds from Withania somnifera target KAT6A through multiple cancer pathways like PI3K-Akt signaling, apoptosis and chemical carcinogenesis. These findings suggest that specific KAT6A mutations may enhance the efficacy of the compounds from W. somnifera. However, further research is needed to validate these results, which could advance clinical applications and drug development for KAT6A-targeted cancer therapies.
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