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- W2944212207 endingPage "5079" @default.
- W2944212207 startingPage "5063" @default.
- W2944212207 abstract "A common source of false positives in drug discovery is ligand self-association into large colloidal assemblies that nonspecifically inhibit target proteins. However, the mechanisms of aggregation-based inhibition (ABI) and ABI-attenuation by additives, such as Triton X-100 (TX) and human serum albumin (HSA), are not fully understood. Here, we investigate the molecular basis of ABI and ABI-attenuation through the lens of NMR and coupled thermodynamic cycles. We unexpectedly discover a new class of aggregating ligands that exhibit negligible interactions with proteins but act as competitive sinks for the free inhibitor, resulting in bell-shaped dose-response curves. TX attenuates ABI by converting inhibitory, protein-binding aggregates into nonbinding coaggregates, whereas HSA minimizes nonspecific ligand interactions by functioning as a reservoir for free inhibitor and preventing self-association. Hence, both TX and HSA are useful tools to minimize false positives arising from nonspecific binding but at the cost of potentially introducing false negatives due to suppression of specific interactions." @default.
- W2944212207 created "2019-05-16" @default.
- W2944212207 creator A5011010472 @default.
- W2944212207 creator A5021126442 @default.
- W2944212207 creator A5024735414 @default.
- W2944212207 creator A5059754670 @default.
- W2944212207 creator A5080619609 @default.
- W2944212207 creator A5091002145 @default.
- W2944212207 date "2019-05-10" @default.
- W2944212207 modified "2023-09-23" @default.
- W2944212207 title "Mechanisms of Specific versus Nonspecific Interactions of Aggregation-Prone Inhibitors and Attenuators" @default.
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