Multiscale computational investigation of β-himachalene oxidation: Density functional theory-based reactivity, chemo- and stereoselectivity, molecular docking, and ADME predictions

Herein, we investigate the oxidation of β-himachalene through a combined approach, involving density functional theory (DFT)-based reactivity descriptors, reaction energy profiles, and molecular docking. The formation of alcohol A1 was found experimentally to have high chemo- and stereoselectivity; a theoretical study was performed to explain the selectivity stemming from kinetic or thermodynamic control. The computed free activation barriers and free energies confirm that the selectivity towards A1 is kinetically controlled, as it was observed experimentally. Moreover, bioinformatics investigation (Pa>0.7) of A1 derivative presented worthy pharmacological acts such as CYP3A4 and CYP2C8 enzymes inhibition, anti-inflammatory (especially MMP9 inhibition), and hormonal regulation (17β-HSD inhibition). These findings were structurally confirmed by molecular docking entry into five selected protein targets, in which stable ligand-protein interactions were used to ascertain the predicted bioactivities. Radar plots and the BOILED-Egg model for absorption, distribution, metabolism, and excretion (ADME) predictions also indicated that the compound exhibits good oral bioavailability and is not likely to penetrate the central nervous system (CNS), which makes it an attractive peripheral therapeutic candidate. Overall, the present study offers detailed insights into the chemo- and stereoselectivity potential and pharmacological possibility of the oxidized β-himachalene derivative.