New natural inhibitors of hexokinase 2 (HK2): Steroids from Ganoderma sinense

Abstract Hexokinase 2 (HK2), a rate-limiting enzyme in the first step of glycolysis pathway, expresses at high level in cancer cells compared with normal cells. HK2 provides a new target for cancer therapy due to its pivotal role in tumor tumourigenic and metastatic process. The structure-based virtual ligand screening in a small in-house database of natural products predicted that a new steroid, (22 E ,24 R )-6 β -methoxyergosta-7,9(11),22-triene-3 β ,5 α -diol ( 2 ) from Ganoderma sinense has high binding affinity to HK2 with significant calculated binding free energy. Based on this prediction, compound 2 , together with the other 12 steroid analogues ( 1 , 3 – 13 ) from this plant were selected for further in vitro microscale thermophoresis (MST), enzyme inhibition, and cell-based assays based on the HK2 target. And compound 2 was finally identified as an HK2 inhibitor. As the first natural HK2 inhibitor, compound 2 can be considered as a potential drug candidate targeting at HK2 for cancer therapy.