Exploring the biological promiscuity of high-throughput screening hits through DFT calculations

The goal of this study is the understanding of biologically promiscuous compounds (frequent hitters) in HTS outcomes through their chemical behavior estimated via reactivity descriptors. Chemical reactivity is often an undesirable property due to the lack in biological selectivity of compounds comprised in HTS libraries. In this study the reactivity indexes have been computed within the DFT formalism, at different levels of theory, for two classes of representative compounds compiled from PubChem database, one comprising frequent hitters and the second one comprising rare hitters (biologically more selective compounds). We found that frequent hitters exert increased reactivity, mainly due to their electrophilic character, compared to the more selective class of compounds.