AUTHOR=Vásquez Andrés Felipe , González Barrios Andrés TITLE=Pushing the Ligand Efficiency Metrics: Relative Group Contribution (RGC) Model as a Helpful Strategy to Promote a Fragment “Rescue” Effect JOURNAL=Frontiers in Chemistry VOLUME=7 YEAR=2019 URL=https://www.frontiersin.org/journals/chemistry/articles/10.3389/fchem.2019.00564 DOI=10.3389/fchem.2019.00564 ISSN=2296-2646 ABSTRACT=

The ligand efficiency (LE) indexes have long been used as decision-making criteria in drug discovery and development. However, in the context of fragment-based drug design (FBDD), these metrics often exhibit a strong emphasis toward the selection of highly efficient “core” fragments for potential optimization, which are not usually considered as parts of a larger molecule with a size typical for a drug. In this study, we present a relative group contribution (RGC) model intended to predict the efficiency of a drug-sized compound in terms of its component fragments. This model could be useful not only in rapidly predicting all the possible combinations of promising fragments from an earlier hit discovery stage, but also in enabling a relatively low-LE fragment to become part of a drug-sized compound as long as it is “rescued” by other high-LE fragments.