Discovery of potent heat shock protein 90 (Hsp90) inhibitors: structure-based virtual screening, molecular dynamics simulation, and biological evaluation

Yonghua Xu; Yunting Zou; Shasha Zhou; Miao-Miao Niu; Yan Zhang; Jindong Li; Zhen Xu; Li Yang

doi:10.1080/14756366.2023.2220558

Discovery of potent heat shock protein 90 (Hsp90) inhibitors: structure-based virtual screening, molecular dynamics simulation, and biological evaluation

J Enzyme Inhib Med Chem. 2023 Dec;38(1):2220558. doi: 10.1080/14756366.2023.2220558.

Authors

Yonghua Xu¹, Yunting Zou², Shasha Zhou¹, Miao-Miao Niu², Yan Zhang³, Jindong Li³, Zhen Xu³, Li Yang³

Affiliations

¹ Department of Pharmacy, Nantong First People's Hospital, Nantong, China.
² Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, China.
³ Department of Oncology, Urology and Pharmacy, The Affiliated Taizhou People's Hospital of Nanjing Medical University, Taizhou, China.

Abstract

Heat shock protein 90 (Hsp90) is considered an attractive therapeutic target for cancer treatment due to its high expression in many cancers. In this study, four potent Hsp90 inhibitors (HPs 1-4) were identified using structure-based virtual screening. Among them, HP-4 exhibited the most potent inhibitory effects (IC₅₀ = 17.64 ± 1.45 nM) against the Hsp90 protein, which was about 7.7 times stronger than that of MPC-3100 (a positive inhibitor targeting Hsp90). In vitro cytotoxicity assay suggested that HP-4 could effectively inhibit the proliferation of a series of tumour cells, including HCT-116, HeLa, A549, A2780, DU145, HepG2 and A498. Furthermore, in vivo assay displayed that HP-4 had significant anti-tumour effects on HCT-116 cell-derived xenograft models. These data demonstrate that HP-4 could be a potential lead compound for the further investigation of anti-tumour drugs.

Keywords: Hsp90; biological evaluation; colon cancer; inhibitor; virtual screening.

MeSH terms

Animals
Cell Line, Tumor
Drug Discovery*
Drug Evaluation, Preclinical / methods
HSP90 Heat-Shock Proteins* / antagonists & inhibitors
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Molecular Docking Simulation
Pharmacophore

Substances

HSP90 Heat-Shock Proteins

Grants and funding

This study is supported by Jiangsu Research Hospital Association for Precision Medication [JY202229] and Fengcheng Talent Plan Youth Science and Technology Talent Recruitment Project of Taizhou [202210].