DFT supported computational insights into Withaferin A structure and its binding interaction with Hsp90.

Withaferin A, a bioactive steroidal lactone, was systematically investigated using density functional theory (DFT) and complementary computational approaches to understand its structural stability, electronic reactivity, and therapeutic potential. The combined spectroscopic and electronic analyses confirmed strong electron delocalization, stable molecular configuration, and favorable charge-transfer characteristics. Natural bond orbital and frontier molecular orbital studies revealed extensive hyperconjugation and high kinetic stability, while thermodynamic assessments indicated spontaneous and stable behavior across varying temperatures. Molecular docking with Hsp90 demonstrated strong binding affinity, stabilized by hydrogen bonding and Van der Waals interactions with key residues. These findings highlight Withaferin A’s structural robustness, electronic versatility, and potent binding characteristics, supporting its promise as a therapeutic inhibitor. Overall, this integrative computational study provides valuable molecular-level insights that can guide future experimental validation and rational drug design involving Hsp90-targeted compounds.