Objective: Our recent studies showed that
desmocollin 1 (DSC1) binds to
apoA-I in order to inhibit
apoA-I-mediated
high density lipoprotein (HDL) biogenesis in
atherosclerotic plaques. To promote HDL biogenesis in the plaque, here we search for small molecules that block apoA-I-DSC1 interactions. Approach and Results: We combined mutational and computational mapping methods to show that
amino acid residues 442-539 in the mature DSC1
protein form an
apoA-I binding site (AIBS). Using a crystal structure of the AIBS, we carried out virtual screening of 10 million small molecules to estimate their binding affinities to the AIBS, followed by the selection of 51 high-affinity binding molecules as potential inhibitors of apoA-I-DSC1 interactions. Among the 51, the
chemotherapy drug docetaxel showed the highest potency in promoting
apoA-I-mediated HDL biogenesis in primary human skin fibroblasts with the half-maximal effective concentration of 0.72 nM. In silico docking studies suggest that the
taxane ring in
docetaxel binds to the AIBS and that the
carbon-13 sidechain of the
taxane tightens/stabilizes the binding. The HDL biogenic effect of
docetaxel was also observed in two predominant cell types in
atherosclerosis, macrophages and smooth muscle cells. Importantly,
docetaxel promoted HDL biogenesis at concentrations much lower than those required for inducing cytotoxicity. Conclusion: Determination of the AIBS in DSC1 and AIBS structure-based virtual screening allowed us to identify
docetaxel as a strong HDL biogenic agent. With the remarkable potency in promoting HDL biogenesis, a
chemotherapy drug docetaxel may be repurposed to enhance atheroprotective HDL functions.