Integrated in silico–in vitro screening of ovarian cancer peroxisome proliferator-activated receptor-γ agonists against a biogenic compound library

Abstract

In recent years, peroxisome proliferator-activated receptor-γ (PPARγ) activation by selective agonists has been emerged as a new and promising strategy for ovarian cancer therapy and prevention. Here, an integrated screening protocol that combined computational protein–ligand binding analysis and cell-based reporter-gene assay was performed against >180,000 biogenic compounds (primary and secondary metabolites) to discover novel potent PPARγ agonists. The screening integrated empirical non-binder exclusion, high-throughput molecular docking, fast affinity scoring, and molecular dynamics simulations to identify promising candidates. Consequently, 12 hits were tested in vitro, from which one and three compounds were found to have high and moderate agonistic potencies for PPARγ with EC₅₀ values at nanomolar and micromolar levels, respectively. Structural bioinformatics analysis revealed a variety of chemical interactions, such as hydrogen bonds, van der Waals contacts, and hydrophobic forces at PPARγ complex interface with the newly identified agonists, conferring both high stability and strong specificity to PPARγ–agonist binding.