Methodology for multi-site ligand-protein docking identification developed for the optimization of spirostenol inhibition of beta-amyloid-induced neurotoxicity.
Spirostenol steroids have been found to inhibit beta-amyloid-induced neurotoxicity. We have evaluated in parallel experimental and molecular-modeling studies the relative effectiveness of 17 (22R)-hydroxycholesterol derivatives in binding to the target peptide. Our results support the previous evidence that beta-amyloid offers multiple docking sites for these steroids. Molecular modeling allowed for the correlation of spirostenol candidate structural differences with a choice of proposed active sites. A multi-site identification technique based on a Site-Identifier Matrix (SIM) was developed that clearly showed the uniqueness of our lead (maximum neurotoxicity inhibition) candidate SP233, with a nearly equal docking affinity for two sites.
Teper
Gary L
GL
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Basic Science Bldg. 3rd Floor, 3900 Reservoir Road NW, Washington, DC 20057, USA.
Lecanu
Laurent
L
Greeson
Janet
J
Papadopoulos
Vassilios
V
D016229:Amyloid beta-Peptides / Q000737:chemistry* / Q000378:metabolism* / Q000633:toxicity; D008024:Ligands; D008958:Models, Molecular; D009433:Neural Inhibition / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013150:Spirostans / Q000737:chemistry*
D016229:Amyloid beta-Peptides; D008024:Ligands; D011506:Proteins; D013150:Spirostans