Correlating structure and energetics in protein-ligand interactions: paradigms and paradoxes

Predicting protein-binding affinities of small molecules, even closely related ones, is a formidable challenge in biomolecular recognition and medicinal chemistry. A thermodynamic approach to optimizing affinity in protein-ligand interactions requires knowledge and understanding of how altering the...

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Bibliographic Details
Published in:Annual review of biochemistry 2013-01, Vol.82 (1), p.267-293
Main Authors: Martin, Stephen F, Clements, John H
Format: Article
Language:English
Subjects:
Biochemistry
Bioenergetics
Crystallography, X-Ray
Entropy
Humans
Hydrophobic and Hydrophilic Interactions
Hydrophobic surfaces
Ligands
Molecular Conformation
Molecules
Protein Binding
Protein Conformation
Proteins
Proteins - chemistry
Proteins - metabolism
Thermodynamics
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Summary:Predicting protein-binding affinities of small molecules, even closely related ones, is a formidable challenge in biomolecular recognition and medicinal chemistry. A thermodynamic approach to optimizing affinity in protein-ligand interactions requires knowledge and understanding of how altering the structure of a small molecule will be manifested in protein-binding enthalpy and entropy changes; however, there is a relative paucity of such detailed information. In this review, we examine two strategies commonly used to increase ligand potency. The first of these involves introducing a cyclic constraint to preorganize a small molecule in its biologically active conformation, and the second entails adding nonpolar groups to a molecule to increase the amount of hydrophobic surface that is buried upon binding. Both of these approaches are motivated by paradigms suggesting that protein-binding entropy changes should become more favorable, but paradoxes can emerge that defy conventional wisdom.
ISSN:0066-4154
1545-4509
DOI:10.1146/annurev-biochem-060410-105819