Systematic Assessment of Molecular Selectivity at the Level of Targets, Bioactive Compounds, and Structural Analogues

Through systematic mining of compound activity data, the target selectivity of bioactive compounds was systematically explored. The analysis was facilitated by applying, extending, and combining the concepts of target cliffs, selectivity cliffs, and matched molecular pairs. Selectivity relationships were explored at different levels including targets, individual bioactive compounds, and pairs of structural analogues. A variety of targets were identified for which active compounds were consistently nonselective or, by contrast, exclusively selective, making it possible to prioritize, or de-prioritize, targets for compound development. Furthermore, many chemical modifications were detected that altered compound selectivity in a well-defined manner including small structural changes that converted nonselective into target-selective compounds or inverted the target selectivity of active compounds. A large knowledge base of selectivity relationships across pharmaceutical targets and chemical modifications that alter selectivity was generated; this has been made freely available to the scientific community as a part of this investigation.