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
  • 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: [email protected].
  • 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: [email protected].
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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