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Fluorescence Anisotropy as a Tool to Study Protein-protein Interactions

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Published on: October 21, 2016

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

Charles H Reynolds¹, Ryan C Reynolds¹

¹Gfree Bio, LLC , 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States.

Journal of Chemical Information and Modeling

|November 8, 2017

Summary

Group additivity, often assumed in drug discovery, is not generally applicable to ligand binding. Analysis reveals binding is nonlinear, necessitating context-specific group additivity schemes for drug design.

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Area of Science:

Biochemistry
Computational Chemistry
Drug Discovery

Background:

Group additivity is a widely used concept for thermochemical and kinetic properties.
In drug discovery, functional group additivity is commonly assumed for ligand binding.
Ligand efficiency can be viewed as a specific application of group additivity.

Purpose of the Study:

To investigate the applicability of group additivity to protein-ligand binding affinities.
To analyze the linearity of ligand binding across diverse protein targets.
To explore the development of group additivity schemes for ligand binding efficiency.

Main Methods:

Analysis of a large dataset of protein-ligand binding affinities (Ki).
Recasting ligand efficiency as a group equivalent (ΔG/HA).
Examination of binding data for diverse protein targets.

Main Results:

Protein-ligand binding affinities are generally nonlinear.
A universal group additivity scheme for ligand binding is not feasible across diverse targets.
Group additivity schemes are viable within closely related protein families.

Conclusions:

The assumption of general group additivity in ligand binding is often invalid.
Drug design requires context-specific approaches, considering protein family and size.
This work provides a foundation for developing more accurate ligand binding efficiency assessment schemes.