2va5
X-RAY CRYSTAL STRUCTURE OF BETA SECRETASE COMPLEXED WITH COMPOUND 8C
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OverviewOverview
Fragment-based lead generation has led to the discovery of a novel series of cyclic amidine-based inhibitors of beta-secretase (BACE-1). Initial fragment hits with an isocytosine core having millimolar potency were identified via NMR affinity screening. Structure-guided evolution of these fragments using X-ray crystallography together with potency determination using surface plasmon resonance and functional enzyme inhibition assays afforded micromolar inhibitors. Similarity searching around the isocytosine core led to the identification of a related series of inhibitors, the dihydroisocytosines. By leveraging the knowledge of the ligand-BACE-1 recognition features generated from the isocytosines, the dihydroisocytosines were efficiently optimized to submicromolar potency. Compound 29, with an IC50 of 80 nM, a ligand efficiency of 0.37, and cellular activity of 470 nM, emerged as the lead structure for future optimization.
About this StructureAbout this Structure
2VA5 is a Single protein structure of sequence from Homo sapiens with and as ligands. Active as Memapsin 2, with EC number 3.4.23.46 Known structural/functional Sites: and . Full crystallographic information is available from OCA.
ReferenceReference
Application of fragment-based lead generation to the discovery of novel, cyclic amidine beta-secretase inhibitors with nanomolar potency, cellular activity, and high ligand efficiency., Edwards PD, Albert JS, Sylvester M, Aharony D, Andisik D, Callaghan O, Campbell JB, Carr RA, Chessari G, Congreve M, Frederickson M, Folmer RH, Geschwindner S, Koether G, Kolmodin K, Krumrine J, Mauger RC, Murray CW, Olsson LL, Patel S, Spear N, Tian G, J Med Chem. 2007 Nov 29;50(24):5912-25. Epub 2007 Nov 7. PMID:17985862
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