The quality of the hits from high-throughput screening (HTS) is often crucial for later success in lead identification and optimization. Consequently pharmaceutical companies have made significant investments in library design, screen optimization, as well as HTS triage. The traditional method of HTS triage to select hits for confirmation is mainly based on the primary activity. The wealth of underlying latent structure-activity relationships between primary active and inactive compounds is thus largely ignored, which could result in the missing of important chemical series, i.e., false negatives. As such, three advanced HTS triage methods were developed to analyze compounds based on their activity neighborhoods populated in the HTS chemical space. Instead of simply using a hard activity cutoff for hit selection, compounds are selected when they are (i) active in the primary screen or (ii) inactive but predicted to be active by neighborhood analysis or Bayesian models. These methods have been applied in the hit selection process for a number of HTS campaigns in multiple therapeutic areas (cardiovascular, inflammation, and neurodegenerative diseases), where numerous false negatives were detected, providing novel chemical and MOA insights for follow-up studies.<br/>

Advanced HTS triage methods to identify false negative compounds

253rd National Meeting (2017)

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