Non-specific colloidal aggregation

Non-specific colloidal aggregation is a physical phenomenon where small molecules self-assemble into particles ranging from 50 to 500 nm in diameter within aqueous assay buffers (McGovern et al., 2002, J. Med. Chem.). These colloids act as promiscuous inhibitors by non-specifically adsorbing and sequestering proteins, leading to false-positive results in biochemical assays (Shoichet, 2006, Drug Discov. Today). This behavior is a significant challenge in high-throughput screening (HTS) and early-stage drug discovery, as it mimics genuine pharmacological activity by causing protein denaturation or sequestration (Coan & Shoichet, 2008, Mol. Pharm.). Unlike specific drug-target interactions, colloidal inhibition is typically sensitive to the addition of non-ionic detergents like Triton X-100, which can disrupt the aggregates and restore enzyme activity (Feng et al., 2005, Nat. Chem. Biol.). Identifying these interactions is essential for distinguishing true lead compounds from assay artifacts and preventing the waste of research resources on non-viable chemical series.

Other names

Colloidal aggregationPromiscuous aggregationNon-specific inhibitionSmall molecule aggregationAggregator-based inhibition

Non-specific protein sequestration and surface-mediated denaturation