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

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:22

Article

Wilfong, Erin M.¹  Du, Yu¹  Toone, Eric J.¹ 

[1] Duke Univ, Dept Chem, Durham, NC 27708 USA

关键词: Additivity;    Fragment based drug design;    Stromelysin-1;    Matrix metalloproteinase-3;   

DOI  :  10.1016/j.bmcl.2012.05.032

来源: Elsevier

【 摘 要 】

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. (c) 2012 Elsevier Ltd. All rights reserved.

【 授权许可】

Free