The BRPF1 protein is encoded by the BRPF1 gene. In addition, the BRPF1 gene is known to be upregulated in leukaemia. Recent studies have shown that it is also overexpressed in hepatocellular carcinoma (HCC) as well. Therefore, BRPF1 is a significant target for anti-cancer drug development studies, especially on HCC. 40 terpenoids and flavonoids were chosen because of their anticancer properties given in the literature. In this study, the biological activity of molecules was also investigated with in silico structure-activity relationship analysis. In addition, interactions between a series of terpenoids and flavonoids and the BRPF1 protein were investigated by molecular docking and molecular dynamics simulations. The energy change caused by the interactions of BRPF1 with different compounds was also evaluated by MM/PBSA calculations. It has been revealed that compound 5 (-9.2 kcal/mol), a kind of secoclerodane type diterpenoid, has a higher affinity both compared to other flavonoids and terpenoids, and 9F9 (-7.9 kcal/mol), a selective BRPF1 inhibitor. The study presented in this article demonstrates that compound 5, as a natural product, could form a chemical scaffold for the development of selective BRPF1 bromodomain inhibitors.