Hispidulin: a potential alternative to vorinostat against HDAC1 for acute myeloid leukemia

Abstract Acute myeloid leukemia (AML) has a survival rate of only 30%, predominantly affecting the bone marrow. AML is characterized by failure of bone marrow function to produce healthy blood cells resulting in significant clinical symptoms such as anemia, shortness of breath, and paleness of skin. This study focuses on elucidating the role of Histone Deacetylase 1 (HDAC1), a critical epigenetic regulator whose dysregulation has been recognized to contribute for AML prognosis. Although vorinostat is a well-established HDAC1 inhibitor, its resistance in cancer cells has necessitated the investigation of anti-leukemic phytochemicals as potential alternative therapeutic agents. A set of 800 unique anti-leukemic phytochemical compounds from 22 Indian plants were screened for pharmacokinetic properties revealed 33 compounds to have inhibitory effects. Further, toxicity screening revealed six compounds hispidulin, kumatakenin, phenyl glycoside, kaempferol, pelargonidin and rohitukine as potential lead candidates. Molecular docking studies indicated hispidulin with a notable binding affinity of -7.8 kcal/mol whereas vorinostat had − 6.51 kcal/mol against HDAC1. Molecular dynamics simulations demonstrated a strong binding affinity of hispidulin to HDAC1, as indicated by an average root mean square deviation (RMSD) of 0.784 nm, an interaction energy (IE) of -208.42 kJ/mol, and a total binding free energy of -28.32 ± 3.23 kcal/mol. In comparison, vorinostat exhibited a higher RMSD of 0.868 nm, a slightly lower IE of -202.04 kJ/mol, and a total binding free energy of -28.39 ± 4.81 kcal/mol. These findings suggest that hispidulin exhibits superior binding stability and interaction strength with HDAC1 relative to vorinostat. Thus, hispidulin may serve as a promising lead compound for HDAC1 modulation, potentially enhancing therapeutic efficacy in the treatment of acute myeloid leukemia (AML).