Ensemble docking for intrinsically disordered proteins.

ABSTRACT: Intrinsically disordered proteins (IDPs) are implicated in many human diseases and are increasingly being pursued as drug targets. Conventional structure-based drug design methods that rely on well-defined binding sites are however, largely unsuitable for IDPs. Here, we present computationally efficient ensemble docking approaches to predict the relative affinities of small molecules to IDPs and characterize their dynamic, heterogenous binding mechanisms at atomic resolution. We demonstrate that these ensemble docking protocols accurately predict the relative binding affinities of small molecule α-synuclein ligands measured by NMR spectroscopy and generate conformational ensembles of ligand binding modes in remarkable agreement with experimentally validated long-timescale molecular dynamic

SUBMITTER: Dhar A 

PROVIDER: S-EPMC11785235 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature