Hybrid structure-based virtual screening protocol for the identification of novel BACE1 inhibitors.
BACE1, also called beta-secretase or memapsin 2, is an extensively studied aspartic protease, involved in etiopathogenesis and progression of Alzheimer's disease (AD). We report herein a modified structure-based virtual screening protocol that augments the lead identification process against BACE1 during virtual screening endeavors. A hybrid structure-based virtual screening protocol that incorporates elements from both ligand-based and structure-based techniques was used for the identification of prospective small molecule inhibitors. Virtual screening, using an active-site-derived pharmacophore, followed by ROCS (rapid overlay of chemical structures)-based GOLD (genetic optimization in ligand docking) docking was used to identify a library of focused candidates. The efficacy of the ROCS-based GOLD docking method together with our customized weighted consensus scoring function was evaluated against conventional docking methods for its ability to discern true positives from a screening library. An in-depth structural analysis of the binding mode of the top-ranking molecules reveals that emulation of the curial interaction patterns deemed necessary for BACE1 inhibition. The results obtained from our validation study ensure the superiority of our docking methodology over conventional docking methods in yielding higher enrichment rates.
Structural Biology and Bioinformatics Division, Indian Institute of Chemical Biology (A unit of CSIR), Kolkata 700032, India.
R S K
RS
Vijayan
M
M
Prabu
Nahren Manuel
NM
Mascarenhas
Nanda
N
Ghoshal
D000544:Alzheimer Disease / Q000201:enzymology; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors*; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D012372:ROC Curve
D004791:Enzyme Inhibitors; D053829:Amyloid Precursor Protein Secretases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human