An enthalpic basis of additivity in biphenyl hydroxamic acid ligands for stromelysin-1.


Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wilfong, EM; Du, Y; Toone, EJ

Published Date

  • October 2012

Published In

Volume / Issue

  • 22 / 20

Start / End Page

  • 6521 - 6524

PubMed ID

  • 22985855

Pubmed Central ID

  • 22985855

Electronic International Standard Serial Number (EISSN)

  • 1464-3405

International Standard Serial Number (ISSN)

  • 0960-894X

Digital Object Identifier (DOI)

  • 10.1016/j.bmcl.2012.05.032


  • eng