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

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 May 5:271:116404. doi: 10.1016/j.ejmech.2024.116404.
Wentao Wang 1,  Siyu Qiu 2,  Tianyi Zhang 1,  Zhiwei Zheng 2,  Kongkai Zhu 3,  Xing Gao 1,  Fengping Zhao 1,  Xinyuan Ma 4,  Hongyan Lin 4,  Yingzi He 5,  Canhui Zheng 6
Affiliations

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.

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