Computational Identification of Indole Alkaloids as Novel Hsp90 ATPase Inhibitors with Anticancer Potential

The ATPase activity of heat shock protein 90 (Hsp90) is crucial for stabilizing and regulating many oncogenic client proteins, thereby supporting cancer progression and tumor cell survival. Although several small-molecule inhibitors have demonstrated preclinical promise, their clinical use remains limited due to toxicity and moderate effectiveness, highlighting the need for new chemotypes with better therapeutic profiles. Indole alkaloids, a diverse group of natural compounds with wide-ranging biological activities—including anticancer, antimicrobial, and enzyme-inhibition effects—were explored here as potential Hsp90 ATPase inhibitors through an extensive computer-based approach. Molecular docking of natural-product derivatives showed strong binding affinities (–10.004 to –10.691 kcal/mol), favorable pharmacokinetic and toxicity predictions, and key interactions with catalytic residues Asp93, Lys58, Gly97, and Thr184. Physicochemical and ADME profiling further validated favorable drug-like properties, including adherence to key medicinal chemistry filters, acceptable solubility, moderate lipophilicity, high oral bioavailability, and no structural alerts. Several indole-alkaloid derivatives also exhibited off-target interactions with several kinases, indicating potential for polypharmacological anticancer effects but emphasizing the importance of selectivity profiling. Overall, this research presents indole alkaloids as promising Hsp90-targeted anticancer candidates. Additional mechanistic studies and preclinical validation are necessary to advance these compounds toward clinical development.