Discovery and Repurposing of Multi-Target Senolytics through Structure-Based Virtual Screening

Abstract

Cellular Senescence is a state of irreversible cell cycle arrest in response to various stressors that can damage the cell. Senescent Cells (SCs) exhibit multiple alterations at the morphological and molecular levels, one of the most significant being the development and activation of Senescent Cell Anti-Apoptotic Pathways (SCAPs). Due to this characteristic, SCs accumulate in organs and tissues during aging. The accumulation of these cells has been associated with the onset and progression of various chronic degenerative diseases, and their selective elimination allows for the slowing down, halting, and reversing of many ageassociated ailments. Small molecules called senolytics, which inhibit SCAPs, have been proposed to selectively eliminate SCs. Herein, we identified new senolytics through computational and rational drug design approaches. Among the identified molecules are the FDA-approved drug tolvaptan, the experimental Phase II drug sotrastaurin, and the experimental drugs cryptotanshinone and bicuculline. The effectiveness of these molecules in targeting senescent cells was confirmed through experiments using two different models of cellular senescence in human lung fibroblasts. Our results suggest that some molecules work by selectively inducing apoptosis through a multi-target mechanism, inhibiting several SCAPs, including PIK3CD, SERPINE1, EFNB1, and PDGFB. These newly identified FDAapproved and experimental drugs have the potential to be repurposed as new senolytic agents.