Comprehensive In silico analysis of chaperones identifies CRYAB and P4HA2 as potential therapeutic targets and their small-molecule inhibitors for the treatment of cholangiocarcinoma.

Cholangiocarcinoma (CCA) is a subtype of liver cancer with increasing incidence, poor prognosis, and limited treatment modalities. It is, therefore, imperative to identify novel therapeutic targets for better management of the disease. Chaperones are known to be significant regulators of carcinogenesis, however, their role in CCA remains unclear. This study aims to screen chaperones involved in CCA pathogenesis and identify drugs targeting key chaperones to improve the therapeutic response to the disease. To achieve this, first we mined the literature to create an atlas of human chaperone proteins. Next, their expression in CCA was determined by publicly available datasets of patients at mRNA and protein levels. In addition, our analysis involving protein-protein interaction and pathway analysis of eight key dysregulated chaperones revealed that they control crucial cancer-related pathways. Furthermore, topology analysis of the CCA network identified crystallin alpha-B protein (CRYAB) and prolyl-4-hydroxylase subunit 2 (P4HA2) as novel therapeutic targets for the disease. Finally, drug repurposing of 286 clinically approved anti-cancer drugs against these two chaperones performed by molecular docking and molecular dynamics simulations showed that tucatinib and regorafenib had a modulatory effect on them and could be potential inhibitors of CRYAB and P4HA2, respectively. Overall, our study, for the first time, provides insights into the pan-chaperone expression in CCA and explains the pathways that might drive CCA pathogenesis. Further, our identification of potential therapeutic targets and their inhibitors could provide new and complementary approaches to CCA treatment.