Virtual Screening and Molecular Docking Characterization of Isoxazole-based Small Molecules as Potential Hsp90 Inhibitors: An in Silico Insight

Abstract

The heat shock protein 90 (Hsp90) is a chaperone machinery implicated in the activity of hundreds of client proteins. Numerous Hsp90 clients have been involved in cancer initiation, progression, and metastasis. Hsp90 becomes more prone to bind to drug-like small molecules in the cancer milieu. Consequently, modulating Hsp90 activity by such molecules is a promising and growing approach for cancer therapy. Isoxazole-based molecules such as Luminespib have exhibited potent inhibitory impacts on Hsp90 activity in myriad human tumor cell lines. In this work, we applied a computer-based protocol to identify isoxazole derivatives to combat Hsp90 oncogenic activity. Screening the ZINC database revealed that thirty-six isoxazole-based molecules can function as Hsp90 inhibitors. Molecular docking simulation analysis demonstrated that twelve of these ZINC compounds have binding energies ranging from −8.23 to −8.51 kcal/mol, which implies a high binding affinity compared to that of Luminespib, with a binding energy of −8.20 kcal/mol. These compounds bind to Hsp90 via hydrogen bonds and hydrophobic interactions with crucial residues such as Gly97, Asn51, and Lys58. Furthermore, several of these compounds have demonstrated their ability to interact with acidic residues on Hsp90 via electrostatic interactions, forming salt bridges. The compounds identified in this study offer a promising foundation for developing potent Hsp90-targeting anticancer agents. To fully evaluate their efficacy in mitigating cancer cell growth, further investigation in cell-based and in vivo models, including optimization of dosing regimens, is warranted.

Received: 15 December 2024 | Revised: 15 April 2025 | Accepted: 29 May 2025

Conflicts of Interest

The author declares that he has no conflicts of interest to this work.

Data Availability Statement

Data sharing is not applicable to this article as no new data were created or analyzed in this study.

Author Contribution Statement

Adam A. Aboalroub: Conceptualization, Methodology, Software, Validation, Formal analysis, Investigation, Data curation, Writing – original draft, Writing – review & editing, Visualization, Supervision, Project administration.