Pros and cons of virtual screening based on public “Big Data”: In silico mining for new bromodomain inhibitors
Iuri Casciuc, Dragos Horvath, Anastasiia Gryniukova, Kateryna A. Tolmachova, Oleksandr V. Vasylchenko, Petro Borysko, Yurii S. Moroz, Jürgen Bajorath, Alexandre A. Varnek · European Journal of Medicinal Chemistry · 2019
The Virtual Screening (VS) study described herein aimed at detecting novel Bromodomain BRD4 binders and relied on knowledge from public databases (ChEMBL, REAXYS) to establish a battery of predictive models of BRD activity for in silico selection of putative ligands. Beyond the actual discovery of new BRD ligands, this represented an opportunity to practically estimate the actual usefulness of public domain “Big Data” for robust predictive model building. Obtained models were used to virtually screen a collection of 2 million compounds from the Enamine company collection. This industrial partner then experimentally screened a subset of 2992 molecules selected by the VS procedure for their high likelihood to be active. Twenty nine confirmed hits were detected after experimental testing, representing 1% of the selected candidates. As a general conclusion, this study emphasizes once more that public structure-activity databases are nowadays key assets in drug discovery . Their usefulness is however limited by the state-of-the-art knowledge harvested so far by published studies. Target-specific structure-activity information is rarely rich enough, and its heterogeneity makes it extremely difficult to exploit in rational drug design . Furthermore, published affinity measures serving to build models selecting compounds to be experimentally screened may not be well correlated with the experimental hit selection criterion (in practice, often imposed by equipment constraints). Nevertheless, a robust 2.6-fold increase in hit rate with respect to an equivalent, random screening campaign showed that machine learning is able to extract some real knowledge in spite of all the noise in structure-activity data. • VS for bromodomain inhibitors utilizes public data sources, assessing their quality. • Rigorous experimental benchmark against random screening under identical conditions. • Virtual hits selected from consensus of GTM (mapping), machine learning, docking. • 29 hits were confirmed, i.e. 2.6 times more than in equivalent random screening. • Heterogeneity of public data and in-house measures negatively impacts enrichment.