Abstract
The heat shock protein 90 (Hsp90) is chaperone machinery involved in the activity of hundreds of client proteins. Numerous Hsp90 clients have been implicated in cancer initiation, progression, and metastasis. Hsp90 becomes more prone to binding to drug-like small molecules in the cancer milieu. Hence, modulating the Hsp90 activity by such molecules is a promising and growing approach for cancer treatment. The isoxazole-based molecules like Luminespib have shown potent inhibitory effects against Hsp90 activity in myriad human tumor cell lines. In this work, the chemical structure of Luminespib was employed to identify new potential Hsp90 inhibitors using a collection of in silico methods. Screening the ZINC database displayed that thirty-six isoxazole-based molecules can function as Hsp90 inhibitors. The molecular docking simulation analysis demonstrated that eleven of these ZINC-compounds have binding energies ranging from -8.00 to -8.42 Kcal/mol, which implies a high binding affinity compared to Luminespib, with a binding energy of -7.95 Kcal/mol. These compounds bind to Hsp90 via hydrogen bonds and hydrophobic interactions with crucial residues like Gly97, Asn51, and Lys58. Further optimization of these ZINC compounds could result in the discovery of potent anticancer agents targeting Hsp90.