title: An enthalpic basis of additivity in biphenyl hydroxamic acid ligands for stromelysin-1.
abstract: Fragment based drug discovery remains a successful tool for pharmaceutical lead discovery. Although based upon the principle of thermodynamic additivity, the underlying thermodynamic basis is poorly understood. A thermodynamic additivity analysis was performed using stromelysin-1 and a series of biphenyl hydroxamate ligands identified through fragment additivity. Our studies suggest that, in this instance, additivity arises from enthalpic effects, while interaction entropies are unfavorable; this thermodynamic behavior is masked by proton transfer. Evaluation of the changes in constant pressure heat capacities during binding suggest that solvent exclusion from the binding site does not account for the dramatic affinity enhancements observed.
authors.affiliation: Department of Chemistry, Duke University, Durham, NC 27708, USA.
authors.forename: Erin M
authors.initials: EM
authors.lastname: Wilfong
authors.forename: Yu
authors.initials: Y
authors.lastname: Du
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Toone
mesh_terms: D001665:Binding Sites; D001713:Biphenyl Compounds / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D006877:Hydroxamic Acids / Q000737:chemistry* / Q000494:pharmacology; D008024:Ligands; D019278:Matrix Metalloproteinase 3 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013816:Thermodynamics
chemical_list: D001713:Biphenyl Compounds; D006877:Hydroxamic Acids; D008024:Ligands; D019278:Matrix Metalloproteinase 3; D061965:Matrix Metalloproteinase Inhibitors; C010574:biphenyl