The clinical drug candidate anle138b binds in a cavity of lipidic α-synuclein fibrils.

ABSTRACT: Aggregation of amyloidogenic proteins is a characteristic of multiple neurodegenerative diseases. Atomic resolution of small molecule binding to such pathological protein aggregates is of interest for the development of therapeutics and diagnostics. Here we investigate the interaction between α-synuclein fibrils and anle138b, a clinical drug candidate for disease modifying therapy in neurodegeneration and a promising scaffold for positron emission tomography tracer design. We used nuclear magnetic resonance spectroscopy and the cryogenic electron microscopy structure of α-synuclein fibrils grown in the presence of lipids to locate anle138b within a cavity formed between two β-strands. We explored and quantified multiple binding modes of the compound in detail using molecular dynamics simul

SUBMITTER: Antonschmidt L 

PROVIDER: S-EPMC9474542 | biostudies-literature | 2022 Sep

REPOSITORIES: biostudies-literature