...Therefore, drugs that increase their stability should have anti-cataract properties. To this end, here we screened 2,560 FDA-approved drugs and natural compounds for their ability to suppress or worsen H2 O2 and/or heat-mediated aggregation of bovine γ-crystallins. The top two drugs, Closantel (C), an anti-helmintic drug, and Gambogic Acid (G), a xanthonoid, attenuated thermal-induced protein unfolding as determined by fluorescence spectroscopy, aggregation as shown by turbidimetry, dynamic light scattering, and electron microscopy of human or mouse recombinant crystallins. Furthermore, binding studies using fluorescence inhibition and hydrophobic pocket-binding molecule bis-ANS revealed static binding of C and G to hydrophobic sites with medium-to-low affinity. Molecular docking to HγD and other γ-crystallins also revealed two binding sites, one in the "NC-pocket" (residues 50-150) of HγD, and one spanning the "NC-tail" (residues 56-61 to 168-174 in the C-terminal domain). Notably, several of these binding sites overlap with those of the protective mini αA-crystallin chaperone peptide, MAC. Mechanistic studies using Bis-ANS as a proxy drug showed it bound to MAC sites, improved Tm of both H2O2 oxidized and native HyD, and suppressed turbidity of oxidized HγD, most likely by trapping exposed hydrophobic sites. The extent to which these drugs act as α-crystallin mimetics and reduce cataract progression remains to be demonstrated. This study provides initial insights into binding properties of C and G to γ-crystallins.