Alzheimer's Disease: Identification and Development of -Secretase (BACE-1) Binding Fragments and Inhibitors by Dynamic Ligation Screening (DLS)

被引:11
|
作者
Fernandez-Bachiller, Maria Isabel [1 ]
Horatscheck, Andre [1 ]
Lisurek, Michael [1 ]
Rademann, Joerg [1 ,2 ]
机构
[1] Leibniz Inst Mol Pharmakol FMP, Dept Med Chem, D-13125 Berlin, Germany
[2] Free Univ Berlin, Inst Pharm, D-14195 Berlin, Germany
关键词
aspartic proteases; drug discovery; FRET; inhibitors; peptides; CLEAVING ENZYME BACE; HUMAN BETA-SECRETASE; STRUCTURE-BASED DESIGN; PROTEASE INHIBITORS; POTENT INHIBITORS; HIGHLY POTENT; DISCOVERY; DERIVATIVES; SUBSTRATE; MECHANISM;
D O I
10.1002/cmdc.201300078
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The application of dynamic ligation screening (DLS), a methodology for fragment-based drug discovery (FBDD), to the aspartic protease -secretase (BACE-1) is reported. For this purpose, three new fluorescence resonance energy transfer (FRET) substrates were designed and synthesized. Their kinetic parameters (Vmax, KM, and kcat) were determined and compared with a commercial substrate. Secondly, a peptide aldehyde was designed as a chemically reactive inhibitor (CRI) based on the Swedish mutation substrate sequence. Incubation of this CRI with the protease, a FRET substrate, and one amine per well taken from an amine library, which was assembled by a maximum common substructure (MCS) approach, revealed the fragment 3-(3-aminophenyl)-2H-chromen-2-one (1) to be a competitive BACE-1 inhibitor that enhanced the activity of the CRI. Irreversibly formed fragment combination products of 1 with the initial peptide sequence were active and confirmed the targeting of the active site through the ethane-1,2-diamine isostere. Finally, structure-assisted combination of fragment 1 with secondary fragments that target the S1 site in hit optimization yielded novel, entirely fragment-based BACE-1 inhibitors with up to 30-fold improved binding affinity. Interactions with the protein were explained by molecular modeling studies, which indicate that the new fragment combinations interact with the catalytic aspartic acid dyad, as well as with the adjacent binding sites required for potency.
引用
收藏
页码:1041 / 1056
页数:16
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