Impact of mutations on KAT6A enzyme and inhibitory potential of compounds from Withania somnifera using computational...

Area of Science:

• Biochemistry and Molecular Biology
• Pharmacology and Drug Discovery
• Computational Chemistry

Background:

• KAT6A (lysine acetyltransferase 6A) is a key enzyme involved in cancer cell proliferation and metastasis.
• Withania somnifera extracts show potential in inhibiting cancer growth by targeting KAT6A.
• The precise impact of KAT6A mutations on enzyme structure and drug interaction remains largely unexplored.

Purpose of the Study:

• To investigate the structural and functional effects of three KAT6A mutations (K181N, R242P, R325C) on its interaction with acetyl-CoA and Withania somnifera-derived inhibitors.
• To assess how these mutations influence the binding affinity and inhibitory potential of Withania somnifera compounds.
• To explore the potential of mutated KAT6A as a therapeutic target for cancer treatment.

Main Methods:

• Molecular docking simulations to predict binding interactions between KAT6A variants, acetyl-CoA, and inhibitors.
• Molecular dynamics simulations to analyze the stability and conformational changes of the enzyme-mutant complexes.
• Network pharmacology to identify cancer-related pathways targeted by Withania somnifera compounds via KAT6A.

Main Results:

• R242P and R325C mutations significantly reduced KAT6A's binding affinity for acetyl-CoA and altered enzyme activity, indicated by increased RMSD values.
• These mutations notably enhanced the inhibitory efficacy of Withania somnifera compounds, especially withanolide E, against KAT6A.
• Mutant KAT6A complexes exhibited higher binding energies with inhibitors and acetyl-CoA compared to wild-type, and network pharmacology confirmed targeting of key cancer pathways.

Conclusions:

• Specific KAT6A mutations (R242P, R325C) can enhance the inhibitory effects of Withania somnifera compounds, suggesting a potential for personalized cancer therapy.
• The findings provide a molecular basis for the increased efficacy of certain natural compounds against mutated KAT6A.
• Further validation is crucial for advancing clinical applications and developing novel KAT6A-targeted cancer therapies.