A Machine Learning Strategy for Drug Discovery Identifies Anti-Schistosomal Small Molecules

• Published in: ACS infectious diseases 2021-02, Vol.7 (2), p.406-420
• Main Authors: Zorn, Kimberley M, Sun, Shengxi, McConnon, Cecelia L, Ma, Kelley, Chen, Eric K, Foil, Daniel H, Lane, Thomas R, Liu, Lawrence J, El-Sakkary, Nelly, Skinner, Danielle E, Ekins, Sean, Caffrey, Conor R
• Format: Article
• Language: English
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.0c00754

Schistosomiasis is a chronic and painful disease of poverty caused by the flatworm parasite Schistosoma. Drug discovery for antischistosomal compounds predominantly employs in vitro whole organism (phenotypic) screens against two developmental stages of Schistosoma mansoni, post-infective larvae (somules) and adults. We generated two rule books and associated scoring systems to normalize 3898 phenotypic data points to enable machine learning. The data were used to generate eight Bayesian machine learning models with the Assay Central software according to parasite’s developmental stage and experimental time point (≤24, 48, 72, and >72 h). The models helped predict 56 active and nonactive compounds from commercial compound libraries for testing. When these were screened against S. mansoni in vitro, the prediction accuracy for active and inactives was 61% and 56% for somules and adults, respectively; also, hit rates were 48% and 34%, respectively, far exceeding the typical 1–2% hit rate for traditional high throughput screens.