4ZPE

BACE1 in complex with 4-(cyclohexylamino)-1-(3-fluorophenyl)-8-(3-isopropoxybenzyl)-1,3,8-triazaspiro[4.5]dec-3-en-2-one

Summary for 4ZPE

• Entry DOI: 10.2210/pdb4zpe/pdb
• Related: 3fkt
• Descriptor: Beta-secretase 1, 4-(cyclohexylamino)-1-(3-fluorophenyl)-8-[3-(propan-2-yloxy)benzyl]-1,3,8-triazaspiro[4.5]dec-3-en-2-one (3 entities in total)
• Functional Keywords: alzheimer disease, amyloid precursor protein secretases, amyloid beta-peptides, aspartic acid endopeptidases, binding sites, drug design, transgenic, models, molecular, protease inhibitors, structure-activity relationship, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Cellular location: Membrane; Single-pass type I membrane protein: P56817
• Total number of polymer chains: 1
• Total formula weight: 45615.38

Authors

Orth, P. (deposition date: 2015-05-07, release date: 2015-08-05, Last modification date: 2015-10-28)

Primary citation

Egbertson, M.,McGaughey, G.B.,Pitzenberger, S.M.,Stauffer, S.R.,Coburn, C.A.,Stachel, S.J.,Yang, W.,Barrow, J.C.,Neilson, L.A.,McWherter, M.,Perlow, D.,Fahr, B.,Munshi, S.,Allison, T.J.,Holloway, K.,Selnick, H.G.,Yang, Z.,Swestock, J.,Simon, A.J.,Sankaranarayanan, S.,Colussi, D.,Tugusheva, K.,Lai, M.T.,Pietrak, B.,Haugabook, S.,Jin, L.,Chen, I.W.,Holahan, M.,Stranieri-Michener, M.,Cook, J.J.,Vacca, J.,Graham, S.L.
Methyl-substitution of an iminohydantoin spiropiperidine beta-secretase (BACE-1) inhibitor has a profound effect on its potency.
Bioorg.Med.Chem.Lett., 25:4812-4819, 2015

PubMed Abstract: The IC50 of a beta-secretase (BACE-1) lead compound was improved ∼200-fold from 11 μM to 55 nM through the addition of a single methyl group. Computational chemistry, small molecule NMR, and protein crystallography capabilities were used to compare the solution conformation of the ligand under varying pH conditions to its conformation when bound in the active site. Chemical modification then explored available binding pockets adjacent to the ligand. A strategically placed methyl group not only maintained the required pKa of the piperidine nitrogen and filled a small hydrophobic pocket, but more importantly, stabilized the conformation best suited for optimized binding to the receptor.

PubMed: 26195137
DOI: 10.1016/j.bmcl.2015.06.082

Experimental method

X-RAY DIFFRACTION (1.7 Å)