Identification of Small-Molecule Modulators of FOXO3 Through Virtual Screening

FOXO3 is integral in regulating numerous genes involved in critical cellular processes such as apoptosis, oxidative damage protection, cell growth, and cancer. Consequently, modulating FOXO3 activity holds significant potential for applications in cancer treatment and cellular aging. A promising approach involves identifying small-molecule modulators that can either enhance or inhibit FOXO3's DNA-binding capability. This paper details a virtual screening protocol aimed at discovering such modulators. Utilizing the crystal structures of FOXO3 in both its free and DNA-bound forms, we pinpoint potential binding sites that may disrupt or facilitate the DNA-FOXO3 interaction. A comprehensive virtual screening of a small-molecule compound library is conducted using AutoDock Vina software. The highest-ranking hits for each site are carefully selected and analyzed to determine their binding modes. This protocol paves the way for identifying novel modulators of FOXO3, offering therapeutic avenues in cancer and aging-related research.