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  2. Structure-based discovery of small molecule inhibitors of FKBP51-Hsp90 protein-protein interaction

Structure-based discovery of small molecule inhibitors of FKBP51-Hsp90 protein-protein interaction

  • Eur J Med Chem. 2024 Mar 28:270:116356. doi: 10.1016/j.ejmech.2024.116356.
Lisha Wang 1 Rajnish Kumar 2 Bengt Winblad 3 Pavel F Pavlov 4
Affiliations

Affiliations

  • 1 Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 17164, Solna, Sweden. Electronic address: lisha.wang@ki.se.
  • 2 Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 17164, Solna, Sweden; Department of Pharmaceutical Engineering & Technology, Indian Institute of Technology (BHU), 221005, Varanasi, India. Electronic address: rajnish.phe@iitbhu.ac.in.
  • 3 Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 17164, Solna, Sweden; Theme Inflammation and Aging, Karolinska University Hospital, 14186, Huddinge, Sweden.
  • 4 Department of Neurobiology, Care Sciences and Society, Division of Neurogeriatrics, Karolinska Institutet, 17164, Solna, Sweden.
Abstract

The heat shock protein 90 kDa (HSP90) molecular chaperone machinery is responsible for the folding and activation of hundreds of important clients such as kinases, steroid hormone receptors, transcription factors, etc. This process is dynamically regulated in an ATP-dependent manner by HSP90 co-chaperones including a group of tetratricopeptide (TPR) motif proteins that bind to the C-terminus of HSP90. Among these TPR containing co-chaperones, FK506-binding protein 51 kDa (FKBP51) is reported to play an important role in stress-related pathologies, psychiatric disorders, Alzheimer's disease, and Cancer, making FKBP51-Hsp90 interaction a potential therapeutic target. In this study, we report identification of potent and selective inhibitors of FKBP51-Hsp90 protein-protein interaction using a structure-based virtual screening approach. Upon in vitro evaluation, the identified hits show a considerable degree of selectivity towards FKBP51 over other TPR proteins, particularly for highly homologous FKBP52. Tyr355 of FKBP51 emerged as an important contributor to inhibitor's specificity. Additionally, we demonstrate the impact of these inhibitors on cellular energy metabolism, and neurite outgrowth, which are subjects of FKBP51 regulation. Overall, the results from this study highlight a novel pharmacological approach towards regulation of FKBP51 function and more generally, HSP90 function via its interaction with TPR co-chaperones.

Keywords

FKBP51; FKBP52; Hsp90; Protein-protein interaction inhibitors; TPR co-chaperones.

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