Journal Article

DZNE-2022-00161

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Molecular Basis of Small-Molecule Binding to α-Synuclein.

Robustelli, P. ; Ibanez de Opakua, A.DZNE* ; Campbell-Bezat, C. ; Giordanetto, F. ; Becker, S. ; Zweckstetter, M.DZNE* ; Pan, A. C. ; Shaw, D. E.

2022
American Chemical Society Washington, DC

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Please use a persistent id in citations: doi:10.1021/jacs.1c07591

Abstract: Intrinsically disordered proteins (IDPs) are implicated in many human diseases. They have generally not been amenable to conventional structure-based drug design, however, because their intrinsic conformational variability has precluded an atomic-level understanding of their binding to small molecules. Here we present long-time-scale, atomic-level molecular dynamics (MD) simulations of monomeric α-synuclein (an IDP whose aggregation is associated with Parkinson's disease) binding the small-molecule drug fasudil in which the observed protein-ligand interactions were found to be in good agreement with previously reported NMR chemical shift data. In our simulations, fasudil, when bound, favored certain charge-charge and π-stacking interactions near the C terminus of α-synuclein but tended not to form these interactions simultaneously, rather breaking one of these interactions and forming another nearby (a mechanism we term dynamic shuttling). Further simulations with small molecules chosen to modify these interactions yielded binding affinities and key structural features of binding consistent with subsequent NMR experiments, suggesting the potential for MD-based strategies to facilitate the rational design of small molecules that bind with disordered proteins.

Keyword(s): 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: analogs & derivatives (MeSH) ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: chemistry (MeSH) ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: metabolism (MeSH) ; Amino Acid Sequence (MeSH) ; Hydrogen Bonding (MeSH) ; Intrinsically Disordered Proteins: chemistry (MeSH) ; Intrinsically Disordered Proteins: metabolism (MeSH) ; Ligands (MeSH) ; Molecular Conformation (MeSH) ; Molecular Dynamics Simulation (MeSH) ; Protein Binding (MeSH) ; Small Molecule Libraries: chemistry (MeSH) ; Small Molecule Libraries: metabolism (MeSH) ; alpha-Synuclein: metabolism (MeSH) ; Intrinsically Disordered Proteins ; Ligands ; Small Molecule Libraries ; alpha-Synuclein ; 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine ; fasudil

Note: (CC BY-NC-ND)

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Contributing Institute(s):

1. Structural Biology in Dementia (AG Zweckstetter)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

Appears in the scientific report 2022

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Database coverage:
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