Figures & data
Figure 1. Reported CARM1 and HDAC inhibitors.
Figure 2. Identification of compounds targeting CARM1/HDAC2 through the integrated screening strategy. (A) Details of the CARM1-based pharmacophore model (F1: H-bond donor feature, F2 and F3: aromatic centre features, F4: hydrophobic centroid feature). Pharmacophore features of CARM1 were represented as spheres. Hydrogen bonds were indicated by dashed black dotted lines. (B) The workflow of combinatorial virtual screening process of dual CARM1/HDAC2-targeting inhibitors. (C) Identification of 7 intersection compounds with lower CARM1-binding energies (< −11.3 kcal/mol) and HDAC2-binding energies (< −11.7 kcal/mol).
Figure 3. The chemical structures of seven compounds (CHs 1–7).
Table 1. The docking scores of CHs 1–7.
Table 2. Pharmacophore model validation by GH score method.
Table 3. The key protein-ligand interactions of CHs 1–7 with CARM1 and HDAC2.
Figure 6. IC50 values of CH-1 and vorinostat for DU145 cells. Data are presented as the mean ± SD, n = 3.
Table 4. Inhibitory effects of CHs 1–7, EZM2302 and vorinostat.
Figure 7. MD simulation of CH-1 in complex with CARM1 and HDAC2. (A) RMSD of CH-1 in CARM1-CH-1 complex. (B) RMSD of CH-1 in HDAC2-CH-1 complex. (C) RMSF of Cα atoms of CARM1 residues in CARM1-CH-1 complex. (D) RMSF of Cα atoms of HDAC2 residues in HDAC2-CH-1 complex. (E,F) The secondary structures analysis of CH-1 in complex with CARM1 and HDAC2, respectively.
Table 5. Cell growth inhibition of CH-1.
Figure 8. The tumour volume changed with time at different CH-1 concentrations. Data are presented as the mean ± SD, n = 3. ***p < 0.001 and **p < 0.01 mean a significant difference versus the vehicle group.
