Identification of small-molecule inhibitors of the steroidogenic acute regulatory protein (STARD1) by structure-based design

Abstract A homology model of the steroidogenic acute regulatory protein (STAR)-related lipid transfer (START) domain of STARD1 was built, and the cholesterol binding site was identified. Structure-based design studies were performed to identify small molecule inhibitors of the START domain. The lead compounds were selected based on cAMP-induced, but not 22R-hydroxycholesterol-supported, inhibition of steroid synthesis by 50% at 10 μM. The results obtained by molecular docking & dynamics show a good correlation between bioactivity, docking scores and calculated binding energies of ligand–protein complexes. The best active compounds will be optimized further and used to develop potential drugs to control excessive steroid formation.