Group Additivity in Ligand Binding Affinity: An Alternative Approach to Ligand Efficiency

Group additivity is a concept that has been successfully applied to a variety of thermochemical and kinetic properties. This includes drug discovery, where functional group additivity is often assumed in ligand binding. Ligand efficiency can be recast as a special case of group additivity where ΔG/H...

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Bibliographic Details
Published in:Journal of chemical information and modeling 2017-12, Vol.57 (12), p.3086-3093
Main Authors: Reynolds, Charles H, Reynolds, Ryan C
Format: Article
Language:English
Subjects:
Affinity
Atomic properties
Atoms & subatomic particles
Binding
Binding sites
Efficiency
Equivalence
Experiments
Functional groups
Hydrogen atoms
Kinetics
Ligands
Proteins
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Summary:Group additivity is a concept that has been successfully applied to a variety of thermochemical and kinetic properties. This includes drug discovery, where functional group additivity is often assumed in ligand binding. Ligand efficiency can be recast as a special case of group additivity where ΔG/HA is the group equivalent (HA is the number of non-hydrogen atoms in a ligand). Analysis of a large data set of protein–ligand binding affinities (K i) for diverse targets shows that in general ligand binding is distinctly nonlinear. It is possible to create a group equivalent scheme for ligand binding, but only in the context of closely related proteins, at least with regard to size. This finding has broad implications for drug design from both experimental and computational points of view. It also offers a path forward for a more general scheme to assess the efficiency of ligand binding.
ISSN:1549-9596
1549-960X
DOI:10.1021/acs.jcim.7b00381