Radical Scavenging and Anti-Ferroptotic Molecular Mechanism of Olanzapine: Insight from a Computational Analysis

Olanzapine is an antipsychotic drug that has been reported to suppress ferroptosis, a recently discovered form of regulated cell death. In this work, the scavenging activity of olanzapine and some of its metabolites is investigated <i>in silico</i> using state-of-the-art density functional theory calculations (level of theory: (SMD)-M06-2X/6-311+G(d,p)//M06-2X/6-31G(d)). Indeed, this reactivity is linked to the therapeutic activity of many antipsychotic drugs and ferroptosis inhibitors. Furthermore, the distinction between hydrogen atom transfer (HAT) and concerted proton coupled electron transfer (cPCET) is elucidated for the most reactive sites of the studied molecules. Then, a promising experimentally guided anti-ferroptotic cyclic mechanism is proposed for ferrostatin-1, a well-known ferroptosis inhibitor, involving the oxidation of Fe^II to Fe^III, the quenching of hydroperoxyl radicals, and the subsequent regeneration of the reactant (level of theory: M06/6-311+G(d,p),def2TZVP//M06/6-31G(d),LANL2DZ). An analogous cyclic process is investigated for liproxstatin-1 and olanzapine, whose activity has been reported in the literature and compared to ferrostatin-1. Finally, the effect of water solvation is evaluated unveiling that the anti-ferroptotic activity of olanzapine is likely less efficient in polar media.