Pushing the ligand efficiency metrics: relative group contribution (RGC) model as a helpful strategy to promote a fragment ‘rescue’ effect

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 towards 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 to rapidly predict all the possible combinations of promising fragments from an earlier hit discovery stage, but also to enable that a relatively low-LE fragment becomes part of a drug-sized compound as long as it is ‘rescued’ by other high-LE fragments.