Quantum chemistry calculation-aided discovery of potent small-molecule mimics of glutathione peroxidases for the treatment of cisplatin-induced hearing loss

Wentao Wang; Siyu Qiu; Tianyi Zhang; Zhiwei Zheng; Kongkai Zhu; Xing Gao; Fengping Zhao; Xinyuan Ma; Hongyan Lin; Yingzi He; Canhui Zheng

doi:10.1016/j.ejmech.2024.116404

Quantum chemistry calculation-aided discovery of potent small-molecule mimics of glutathione peroxidases for the treatment of cisplatin-induced hearing loss

Eur J Med Chem. 2024 Apr 12:271:116404. doi: 10.1016/j.ejmech.2024.116404. Online ahead of print.

Authors

Wentao Wang¹, Siyu Qiu², Tianyi Zhang¹, Zhiwei Zheng², Kongkai Zhu³, Xing Gao¹, Fengping Zhao¹, Xinyuan Ma⁴, Hongyan Lin⁴, Yingzi He⁵, Canhui Zheng⁶

Affiliations

¹ The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University (Second Military Medical University), Shanghai, 200433, China.
² ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai, 200031, China.
³ Advanced Medical Research Institute, Cheeloo College of Medicine, Shandong University, Jinan, 250012, China.
⁴ School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200031, China.
⁵ ENT Institute and Department of Otorhinolaryngology, Eye & ENT Hospital, State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Fudan University, NHC Key Laboratory of Hearing Medicine (Fudan University), Shanghai, 200031, China. Electronic address: yingzihe09611@126.com.
⁶ The Center for Basic Research and Innovation of Medicine and Pharmacy (MOE), School of Pharmacy, Naval Medical University (Second Military Medical University), Shanghai, 200433, China. Electronic address: canhuizheng@smmu.edu.cn.

PMID: 38631262
DOI: 10.1016/j.ejmech.2024.116404

Abstract

Hearing loss (HL) is a health burden that seriously affects the quality of life of cancer patients receiving platinum-based chemotherapy, and few FDA-approved treatment specifically targets this condition. The main mechanisms that contribute to cisplatin-induced hearing loss are oxidative stress and subsequent cell death, including ferroptosis revealed by us as a new mechanism recently. In this study, we employed the frontier molecular orbital (FMO) theory approach as a convenient prediction method for the glutathione peroxidase (GPx)-like activity of isoselenazolones and discovered new isoselenazolones with great GPx-like activity. Notably, compound 19 exhibited significant protective effects against cisplatin-induced hair cell (HC) damage in vitro and in vivo and effectively reverses cisplatin-induced hearing loss through oral administration. Further investigations revealed that this compound effectively alleviated hair cell oxidative stress, apoptosis and ferroptosis. This research highlights the potential of GPx mimics as a therapeutic strategy against cisplatin-induced hearing loss. The application of quantum chemistry (QC) calculations in the study of GPx mimics sheds light on the development of new, innovative treatments for hearing loss.

Keywords: Cisplatin-induced hearing loss; Ferroptosis; Frontier molecular orbital; Glutathione peroxidases mimics; Oxidative stress.