Related Experiment Video
Updated: Mar 2, 2026
10:13
Measuring G-protein-coupled Receptor Signaling via Radio-labeled GTP Binding
Published on: June 9, 2017
17.4K
Between Descriptors and Properties: Understanding the Ligand Efficiency Trends for G Protein-Coupled Receptor and
Jaroslaw Polanski1, Aleksandra Tkocz1
1Institute of Chemistry, University of Silesia , 9 Szkolna Street, 40-006 Katowice, Poland.
Journal of Chemical Information and Modeling
|May 11, 2017
Summary
Ligand efficiency (LE) is a statistical property, not a molecular descriptor. This finding reevaluates its use in drug optimization by considering Avogadro statistics and non-binding effects.
Area of Science:
- Medicinal Chemistry
- Computational Chemistry
- Pharmacology
Background:
- Ligand efficiency (LE) is widely used in early drug optimization as an estimator of binding potency.
- Controversy exists regarding the mathematical validity and performance of LE metrics in drug discovery.
- Current interpretations of LE often misunderstand its chemical meaning, linking it to single molecular properties.
Purpose of the Study:
- To clarify the chemical meaning of ligand efficiency (LE) metrics.
- To explain the statistical basis of LE using G protein-coupled receptor (GPCR) and kinase structure-activity data.
- To address the common misinterpretation of LE as a descriptor of a single molecule's binding potency.
Main Methods:
- Analysis of a large dataset of G protein-coupled receptor (GPCR) and kinase structure-activity relationships (IC50, Ki).
- Statistical regression of binding properties against heavy atom count (HAC).
- Investigation of the correlation between LE and molecular weight due to Avogadro statistics.
Main Results:
- Ligand efficiency (LE) is demonstrated to be a statistical property, not a descriptor of a single molecule.
- LE is correlated with the reciprocal of molecular weight due to Avogadro statistics.
- The observed hyperbolic model of LE arises from a non-binding effect related to ligand availability, not increased binding potency per HAC.
Conclusions:
- The interpretation of LE as a molecular descriptor for a single molecule is fundamentally flawed.
- LE should be understood as a statistical property influenced by molecular size and ligand pool effects.
- Reevaluation of LE-based molecular comparisons is necessary for accurate drug optimization strategies.
Related Concept Videos
01:15G Protein-coupled Receptors
18.4K
G Protein-Coupled Receptors or GPCRs are membrane-bound receptors that transiently associate with heterotrimeric G proteins and induce an appropriate response to sensory stimuli such as light, odors, hormones, cytokines, or neurotransmitters.
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
GPCRs are also called heptahelical, 7TM, or serpentine receptors, and consist of seven (H1-H7) transmembrane alpha-helices that span the bilayer to form a cylindrical core. The transmembrane helices are connected by three extracellular loops and three...
18.4K
02:40Ligand Binding Sites
15.4K
Proteins are dynamic macromolecules that carry out a wide variety of essential processes; however, the activities of most proteins depend on their interactions with other molecules or ions, known as ligands.
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
Protein-ligand interactions are quite specific; even though numerous potential ligands surround a cellular protein at any given time, only a particular ligand can bind to that protein. Moreover, a ligand binds only to a dedicated area on the surface of the protein, known as the...
15.4K
02:40Ligand Binding Sites
9.0K
9.0K
02:18The Equilibrium Binding Constant and Binding Strength
15.4K
The equilibrium binding constant (Kb) quantifies the strength of a protein-ligand interaction. Kb can be calculated as follows when the reaction is at equilibrium:
15.4K
01:29The Two-State Receptor Model
3.3K
The two-state receptor model explains a drug's interaction with receptors, such as G protein-coupled receptors and ligand-gated ion channels, to induce or inhibit a biological response. When no natural ligands are present, a receptor exists in an equilibrium of inactive (Ri) and active (Ra) conformations. The inactive form does not produce a response, while the active form generates a basal effect known as constitutive activity.
The binding affinity of a drug determines its interaction with...
The binding affinity of a drug determines its interaction with...
3.3K
00:49Ligand Binding and Linkage
5.7K
Allosteric proteins have more than one ligand binding site; the binding of a ligand to any of these sites influences the binding of ligands to the other sites. When a protein is allosteric, its binding sites are called coupled or linked. In the case of enzymes, the site that binds to the substrate is known as the active site and the other site is known as the regulatory site. When a ligand binds to the regulatory site, this leads to conformational changes in the protein that can influence...
5.7K