Identification of New CD36 Antagonists by Structure-Based Virtual Screening.

CD36 is a transmembrane glycoprotein that facilitates the uptake of fatty acids and oxidized low-density lipoproteins. CD36 is overexpressed in various types of cancer and CD36(+) cancer cells display enhanced malignancy, including resistance to therapy and elevated stemness and metastatic ability. Thus, CD36 is a therapeutic target in cancer. This study aimed to discover new CD36 antagonists through virtual screening. We identified a druggable pocket in CD36 that is functionally relevant and serves as the binding site for reported antagonists. Consensus molecular docking of a chemical library containing over 25,000 drug-like compounds identified 15 computational hits with structural diversity. Experimental evaluation of seven compounds revealed that compounds 8, 13, and 14 are novel inhibitors of CD36-mediated palmitate and/or oxLDL uptake in cellular models. Compound 14 reduced the clonogenicity of HepG2 cells without impacting cell viability, showing that it modulates CD36-triggered phenotypes associated with disease progression. Analysis of molecular interactions of compounds 8, 13, or 14 with CD36 by molecular dynamics simulations showed that the identified antagonists had stable binding and favorable binding energy, leading to distinct conformational states of the protein. These results support the use of the antagonists identified here as lead compounds for developing CD36-targeted therapies.