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

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 mu M. 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. (C) 2012 Elsevier Ltd. All rights reserved.