title: 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.
authors.affiliation: The Research Institute of the McGill University Health Centre, McGill University, Montreal, Quebec, Canada H3G1A4.
authors.forename: Nagaraju
authors.initials: N
authors.lastname: Akula
authors.forename: Andrew
authors.initials: A
authors.lastname: Midzak
authors.forename: Laurent
authors.initials: L
authors.lastname: Lecanu
authors.forename: Vassilios
authors.initials: V
authors.lastname: Papadopoulos
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002784:Cholesterol / Q000737:chemistry* / Q000378:metabolism; D000242:Cyclic AMP / Q000737:chemistry*; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D007985:Leydig Cells / Q000187:drug effects / Q000378:metabolism; D008024:Ligands; D008297:Male; D051379:Mice; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D010750:Phosphoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000494:pharmacology; D040681:Structural Homology, Protein; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D000098682:Steroidogenic Acute Regulatory Protein
chemical_list: D008024:Ligands; D010750:Phosphoproteins; D054852:Small Molecule Libraries; D000098682:Steroidogenic Acute Regulatory Protein; D002784:Cholesterol; D000242:Cyclic AMP