Strategy of Virtual Screening based Discovery of HSP90 C-terminal Inhibitors and Network Pharmacological Analysis

Background: HSP90 has been considered an important anticancer target for several decades, but traditional HSP90 N-terminal inhibitors often suffered from organ toxicity and/or drug resistance.

Methods: The development of HSP90 C-terminal inhibitors represents a reliable alternative strategy. In view of rare examples of structure-based identification of HSP90 C-terminal inhibitors, we report a virtual screening based strategy for the discovery of HSP90 C-terminal inhibitors as anticancer agents from natural products.

Results & discussion: 13 chemical ingredients from licorice were identified as possible HSP90 inhibitors and 3 of them have been reported as anticancer agents. The binding modes towards HSP90 C-terminus were predicted by molecular docking and refined by molecular dynamics simulation.

Conclusion: Further network pharmacological analysis predicted overall possible targets involved in the pathways in cancer and revealed that 8 molecules possibly interact with HSP90. A structure based virtual screening strategy was established for the discovery of HSP90 Cterminal inhibitors.