title: Correlating structure and energetics in protein-ligand interactions: paradigms and paradoxes.
abstract: 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.
authors.affiliation: Department of Chemistry and Biochemistry, Institute of Cellular and Molecular Biology, University of Texas, Austin, Texas 78712, USA. sfmartin@mail.utexas.edu
authors.forename: Stephen F
authors.initials: SF
authors.lastname: Martin
authors.forename: John H
authors.initials: JH
authors.lastname: Clements
mesh_terms: D018360:Crystallography, X-Ray; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D008968:Molecular Conformation; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D008024:Ligands; D011506:Proteins