Determination of anticancer activity and mechanism of action of benzooxazepines (BZOs) derivatives using multipronged computational and structural approaches

[Display omitted] In this study, the molecular descriptors (MDs) of a set of halogenated benzooxazepines (BZOs) were evaluated to determine their absorption, distribution, metabolism, excretion, and toxicity properties. Molecular docking and dynamics analyses were performed to investigate the action mechanisms. The optimization of BZOs was carried out using density function theory with Becke’s three parameter hybrid functional (B3LYP) at the 6-31G+(d,p) level. Which was further correlated with theoretical and experimental spectroscopic values. Detailed studies were performed on frontier molecular orbitals, quantum chemical descriptors, IR, and NMR spectroscopy. A preliminary structure–activity relationship analysis revealed that BZOs bearing Cl substitution had greater effectiveness, particularly when positioned at the R2-position on the BZO-e system. Further BZOs were used as inhibitors of apoptosis pathway-related protein targets, including caspase 8, caspase 3, Bcl-2, Bcl-xl, BAD, BAX, apoptotic protease-activating factor 1, poly [ADP-ribose] polymerase 1 (PARP1), and tankyrase 1 for potential anticancer activity. The stability of the receptor-inhibitor complex was validated by the molecular dynamics analysis of the PARP1 complex.