Design and interaction mechanism of novel SIRT1 inhibitors for the treatment of hepatocellular carcinoma†

Silent information regulator sirtuin 1 (SIRT1) is a niacinamide adenine dinucleotide (NAD)-dependent histone deacetylase and a promising target for the treatment of hepatocellular carcinoma (HCC). In this research, we designed SIRT1 inhibitors using various computational methods and validated their activity through experiments, while network pharmacology was used to explore the potential therapeutic effects of the designed compounds on HCC. Based on the 3D-QSAR contour map, pharmacophore, MOLCAD and ADMET analysis results, we attempted to construct seven compounds. Among them, compound 18a showed excellent predictive activity and pharmacokinetic properties. The molecular dynamics (MD) simulations indicated that compound 18a binds closely to the SIRT1 protein. PHE57, PHE33, ILE107 and ILE30 were considered to be key residues that facilitated the binding of the ligand to the receptor. Integrating experimental results and network pharmacology predictions indicated that compound 18a exerted its inhibitory effect on the proliferation of HCC possibly by regulating the FOXO signaling pathway and the PI3K-Akt signaling pathway. This study provides theoretical support for the design and discovery of novel SIRT1 inhibitors.