Ligand efficiency metrics: why all the fuss?

Abstract

Ligand efficiency (LE) is most commonly defined as the ratio of the affinity of a ligand divided by the number of heavy (nonhydrogen) atoms in the molecule (LE = ΔG/[number of heavy atoms]). This ratio was first described in 1999 [1] and gained widespread popularity in drug discovery circles shortly thereafter [2]. The rapid uptake of LE in drug discovery was likely facilitated by the already widespread use of Lipinski’s rules (another size restraining metric) [3] and a burgeoning interest in fragment-based approaches to drug discovery [4]. Ligand efficiency validated fragment-based design and offered a simple measure to keep molecular size in check while undertaking a lead optimization program. Like the rule of five, the rapid adoption of LE by medicinal chemists was probably aided by the simplicity of the metric (no need for complicated algorithms) and the fact that it neatly captured a compelling concept: namely that it is in general better to bring drug discovery candidates forward that are small rather than large. Indeed, many of the productivity problems plaguing the industry are sometimes ascribed to the growing number of potent ‘rocks’ being produced by discovery efforts driven by in vitro biology [5]. Simple metrics, like LE or the rule of five, help bring the problem of molecular size inflation into focus, in a way that is easy to understand. Ligand efficiency has been reviewed recently [6], and the reader is referred to that paper for a detailed description of its many flavors (e.g., LE and lipophilic ligand efficiency [LLE]). The review describes the most common efficiency measures in detail, provides references to examples of their application and compares the advantages and disadvantages of different metrics.