ci7b00116_si_001.pdf (2.12 MB)
Download file

Between Descriptors and Properties: Understanding the Ligand Efficiency Trends for G Protein-Coupled Receptor and Kinase Structure–Activity Data Sets

Download (2.12 MB)
journal contribution
posted on 10.05.2017, 00:00 by Jaroslaw Polanski, Aleksandra Tkocz
The chemical meaning of the ligand efficiency (LE) metrics is explained in this paper using a large G protein-coupled receptor (GPCR) and kinase structure–activity (IC50, Ki) data set. Although there is a controversy in the literature regarding both the mathematical validity and the performance of LE, it is in common use as an early estimator for drug optimization. Apparently, the numerous con arguments are not convincing enough. We show here for the first time that the main misunderstanding of the chemical meaning of LE is its interpretation as a molecular descriptor connected with a single molecule. Instead, LE should be interpreted as a statistical property. We show that the LE, which is designed as a regression of a binding property on the heavy atom count (HAC), is correlated to the reciprocal of the molecular weight because of Avogadro statistics. This indicates that the hyperbolic model of LE is basically a consequence of a nonbinding effect, an increase in the number of ligands that are available to a receptor for smaller molecules, and not a real increase in the binding potency for a single HAC as interpreted in the literature. Accordingly, we need to revisit and carefully reevaluate LE-based molecular comparisons.