Identification of nucleotide binding sites and repurposing of potential FDA-approved inhibitors against human HOP

HSP70-HSP90 organizing protein (HOP) is a molecular co-chaperone that mediates the transfer of client proteins, including oncogenic proteins, for folding from HSP70 to HSP90 via a cycle of ATP binding, hydrolysis, and nucleotide exchange. Targeting HOP using small molecules can alter this protein folding cycle and reduce/prevent the folding of oncogenic proteins. The current study explored the computational tools to predict the nucleotide (ATP and GTP) binding site on HOP via sequence and structure-based approaches. It screened FDA-approved compounds for repurposing as inhibitors against HOP using molecular docking, molecular dynamics simulations, DFT, and end-state binding free energy calculations, and identified the top 10 potential inhibitors of HOP. The network pharmacology of these top 10 screened inhibitors highlights many other target proteins involved in cancer. This is the first computational study to identify critical residues of HOP engaged in interactions with ATP and GTP, which can be targeted to design novel inhibitors of HOP. Among the top 10 compounds (Atovaquone, Bicalutamide, Celecoxib, Dexamethasone, Glimepiride, Imipenem, Saxagliptin, Tadalafil, Tarceva, and Indinavir), Tarceva (Erlotinib) and Indinavir emerged as particularly promising, potentially binding to the TPR2A and TPR2B-DP2 domains, respectively. Molecular electrostatic potential surface (MESP) analysis further supported these interactions, showing that Tarceva’s predominantly negative charge aligns with TPR2A’s positive binding groove, while Indinavir’s positive surface complements the negatively charged binding groove of the DP2-TPR2B domain. Our results show that Tarceva (Erlotinib) and Indinavir may inhibit the interaction of HOP with HSP70-90 (Heat Shock Protein 70–90). Further, this study may also provide a template to design more potent drug analogues against different domains of HOP. While these findings present promising avenues for targeting HOP in cancer treatment, additional in vitro and in vivo validations are required before these repurposed inhibitors can be effectively used to inhibit HSP70-HOP and HSP90-HOP protein-protein interactions.