The concurrent docking of diphenoquinone and cholesterol to the human ATP-binding cassette A1

Aim: Spiroquinone (SQ) and 3,3',5,5'-tetra-tert-butyldiphenoquinone (DQ), metabolites of the probucol, promote ABCA1-mediated HDL neogenesis. To further investigate the detailed mechanism, we analyzed the docking pose of these drugs to ABCA1 using GOLD (Genetic Optimization for Ligand Docking) software, an in silico structural analysis application. Then, docking ability of cholesterol to the drug-ABCA1 complex were investigated. Methods: The ligand-bound ABCG2 (PDB:6ETI) was used for ligand redocking to select the optimal scoring function of GOLD. Next, human ABCA1 (PDB:5XJY) was used and the docking poses of probucol, SQ, DQ, and MDL-29311 were examined using the selected scoring function. Furthermore, binding poses of cholesterol and POPC to the drug-docked ABCA1 complex were evaluated. Results: The ChemScore function was the most accurate predictor of the original docking site of the ligand to ABCG2. Using this function to predict the docking calculations for ABCA1, optimal docking poses was obtained at the transmembrane region. Furthermore, docking poses for cholesterol were predicted into ABCA1 bound to DQ and to MDL-29311(fitness score; 41.42 and 41.61, respectively) while no docking poses in probucol- or SQ-bound ABCA1 were obtained. Discussion: We reported that DQ, an accelerator of the preb-HDL generation, stabilizes ABCA1 and sustains HDL neogenesis(1). In the current study, in addition to DQ docking pose, docking sites of cholesterol and POPC were observed in ABCA1 in silico . Furthermore, probucol, which inhibits ABCA1-mediated preb-HDL neogenesis, showed no additional docking sites for cholesterol or POPC. Conclusion: These results are the first to elucidate the at atomic level of the mechanism in lipid transport action of probucol and its metabolite, DQ, on ABCA1. Future clinical applications of DQ for targeting the increased plasma HDL and regression of atherosclerotic plaques are expected.