Fisetin as a Blueprint for Senotherapeutic Agents - Elucidating Geroprotective and Senolytic Properties with...

Targeting senescent cells and the factors that accelerate this pathological state has recently emerged as a novel field in medicinal chemistry. As attention shifts to synthetic substances, studies on natural agents are often overlooked. In this paper, we present a detailed computational modeling study that encompasses quantum mechanics and molecular dynamics to elucidate the senotherapeutic activity of fisetin, a natural flavonoid. The mitochondrial environment, serving as a proxy for senescence, received special attention. Throughout the study, fisetin's outstanding geroprotective properties-exhibiting significant potential against ⋅OOH, O₂⋅^-, and ⋅OH radicals, surpassing those of Trolox or ascorbate-were identified. Furthermore, fisetin demonstrated a high capacity to restore oxidatively damaged biomolecules to their pristine forms, thereby renewing the functionality of proteins and amino acids. The senolytic properties were examined in terms of Bcl-2 and Bcl-xL inhibition. The results indicated that fisetin not only binds effectively to these proteins but also, with appropriate modifications, may exhibit specific selectivity toward either target. This study highlights fisetin's remarkable activity in these areas and provides a molecular description of the underlying processes, paving the way for future research.