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Fragment Binding to beta-Secretase 1 without Catalytic Aspartate Interactions Identified via Orthogonal Screening Approaches

Fecha de publicación:

Autores de IIS La Fe

Participantes ajenos a IIS La Fe

  • Rombouts, FJR
  • Alexander, R
  • Cleiren, E
  • De Groot, A
  • Carpentier, M
  • Dijkmans, J
  • Fierens, K
  • Masure, S
  • Moechars, D
  • Trabanco, AA
  • Van Glabbeek, D
  • Vos, A
  • Tresadern, G

Grupos

Abstract

An approach to identify beta-secretase 1 (BACE1) fragment binders that do not interact with the catalytic aspartate dyad is presented. A ThermoFluor (thermal shift) and a fluorescence resonance energy transfer enzymatic screen on the soluble domain of BACE1, together with a surface plasmon resonance (SPR) screen on the soluble domain of BACE1 and a mutant of one catalytic Asp (D32N), were run in parallel. Fragments that were active in at least two of these assays were further confirmed using one-dimensional NMR (WaterLOGSY) and SPR binding competition studies with peptidic inhibitor OM99-2. Protein-observed NMR (twodimensional N-15 heteronuclear single-quantum coherence spectroscopy) and crystallographic studies with the soluble domain of BACE1 identified a unique and novel binding mode for compound 12, a fragment that still occupies the active site while not making any interactions with catalytic Asps. This novel approach of combining orthogonal fragment screening techniques, for both wild-type and mutant enzymes, as well as binding competition studies could be generalized to other targets to overcome undesired interaction motifs and as a hit-generation approach in highly constrained intellectual property space.

Datos de la publicación

ISSN/ISSNe:
2470-1343, 2470-1343

Acs Omega  AMER CHEMICAL SOC

Tipo:
Article
Páginas:
685-697
PubMed:
28626832
Factor de Impacto:
0,749 SCImago ℠
Cuartil:
Q1 SCImago ℠

Citas Recibidas en Web of Science: 11

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Keywords

  • AMYLOID CASCADE HYPOTHESIS; STRUCTURE-BASED DESIGN; ALZHEIMERS-DISEASE; DRUG DISCOVERY; BACE1 INHIBITORS; PRECURSOR PROTEIN; ENZYME; THERAPEUTICS; PURIFICATION; GENERATION

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