SCAM Detective: Accurate Predictor of Small, Colloidally Aggregating Molecules

Small, colloidally aggregating molecules (SCAMs) are the most common source of false positives in high-throughput screening (HTS) campaigns. Although SCAMs can be experimentally detected and suppressed by the addition of detergent in the assay buffer, detergent sensitivity is not routinely monitored in HTS. Computational methods are thus needed to flag potential SCAMs during HTS triage. In this study, we have developed and rigorously validated quantitative structure-interference relationship (QSIR) models of detergent-sensitive aggregation in several HTS campaigns under various assay conditions and screening concentrations. In particular, we have modeled detergent-sensitive aggregation in an AmpC beta-lactamase assay, the preferred HTS counter-screen for aggregation, as well as in another assay that measures cruzain inhibition. Our models increase the accuracy of aggregation prediction by similar to 53% in the beta-lactamase assay and by similar to 46% in the cruzain assay compared to previously published methods. We also discuss the importance of both assay conditions and screening concentrations in the development of QSIR models for various interference mechanisms besides aggregation.