Between Descriptors and Properties: Understanding
the Ligand Efficiency Trends for G Protein-Coupled Receptor and Kinase
Structure–Activity Data Sets
Jaroslaw Polanski
Aleksandra Tkocz
10.1021/acs.jcim.7b00116.s001
https://acs.figshare.com/articles/journal_contribution/Between_Descriptors_and_Properties_Understanding_the_Ligand_Efficiency_Trends_for_G_Protein-Coupled_Receptor_and_Kinase_Structure_Activity_Data_Sets/5026598
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 (IC<sub>50</sub>, <i>K</i><sub>i</sub>) 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.
2017-05-10 00:00:00
LE
Ligand Efficiency Trends
GPCR
G protein-coupled receptor
HAC
IC
chemical meaning
G Protein-Coupled Receptor