Molecular modeling of 7-propanamide benzoxaboroles as CPSF3 inhibitors through docking-based 3D-QSAR and molecular dynamics simulations.

Benzoxaboroles are boron-based heterocycles with broad therapeutic potential, including two FDA-approved drugs, tavaborole and crisaborole. It was reported that the discovery of 7-propanamide benzoxaboroles as novel potent anti-cancer agents, with compound 44 inhibiting cleavage and polyadenylation specific factor 3 (CPSF3), a key mRNA processing enzyme. By blocking CPSF3's RNA-binding function, compound 44 disrupts pre-mRNA cleavage and induces cancer cell death. In our current study, we systematically investigated the structure-activity relationships (SARs) of a series of 7-propanamide benzoxaboroles using docking-based three-dimensional quantitative structure-activity relationship (3D-QSAR). Comparative molecular field analysis (CoMFA, r 2 = 0.937, q 2 = 0.826) and comparative molecular similarity indices analysis (CoMSIA, r 2 = 0.964, q 2 = 0.882) reveals critical structural determinants for CPSF3 binding and inhibition. Additionally, molecular dynamics (MD) simulations were used to better understand the important molecular interactions between the inhibitors and CPSF3, such as metal-mediated coordination, Phe238-mediated pi-pi stacking, van der Waals interactions and hydrophobic embedding mediated by hydrophobic amino acids. Guided by the obtained SAR, we designed a series of seven novel derivatives featuring the 7-propanamide benzoxaborole scaffold. Among them, compounds 50 and 51 show enhanced pIC50 values compared to compound 32. In conclusion, this study explores SARs of benzoxaborole compounds through docking-based 3D-QSAR and MD simulations, offering valuable theoretical guidance for the rational design of new benzoxaborole derivatives as anti-cancer agents via inhibiting CPSF3.