Hybrid Structure-Based Virtual Screening Protocol for the Identification of Novel BACE1 Inhibitors
IR@IICB: CSIR-Indian Institute of Chemical Biology, KolkataView Archive Info
Hybrid Structure-Based Virtual Screening Protocol for the Identification of Novel
Vijayan, R S K
Manuel Mascarenhas, Nahren
Structural Biology & Bioinformatics
BACE1, also called �-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 ligandbased
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.
Vijayan, R S K and Prabu, M and Manuel Mascarenhas, Nahren and Ghoshal, Nanda (2009) Hybrid Structure-Based Virtual Screening Protocol for the Identification of Novel BACE1 Inhibitors. Journal of Chemical Information and Modeling, 49. pp. 647-657.
http://dx.doi.org/10.1021/ci800386v CCC: $40.75