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Methodology for Multi‐Site Ligand–Protein Docking Identification Developed for the Optimization of Spirostenol Inhibition of β ‐Amyloid‐Induced Neurotoxicity
Author(s) -
Teper Gary L.,
Lecanu Laurent,
Greeson Janet,
Papadopoulos Vassilios
Publication year - 2005
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200590128
Subject(s) - neurotoxicity , docking (animal) , chemistry , binding site , amyloid beta , active site , biochemistry , stereochemistry , computational biology , peptide , enzyme , toxicity , biology , medicine , nursing , organic chemistry
Spirostenol steroids have been found to inhibit β ‐amyloid‐induced neurotoxicity. We have evaluated in parallel experimental and molecular‐modeling studies the relative effectiveness of 17 (22 R )‐hydroxycholesterol derivatives in binding to the target peptide. Our results support the previous evidence that β ‐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.