Department of Chemistry, Duke University, Durham, NC 27708, USA.
Bioorg Med Chem Lett. 2012 Oct 15;22(20):6521-4. doi: 10.1016/j.bmcl.2012.05.032. Epub 2012 May 30.
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.
基于片段的药物发现仍然是药物先导化合物发现的一种成功工具。尽管基于热力学加和性的原则，但对其基础热力学原理的理解还很不完善。本研究采用基质金属蛋白酶-1和一系列通过片段加和性鉴定的联苯羟肟酸配体进行了热力学加和性分析。我们的研究表明，在这种情况下，加和性来自焓效应，而相互作用熵是不利的；质子转移掩盖了这种热力学行为。结合过程中恒压热容变化的评估表明，结合部位的溶剂排除并不能解释观察到的显著亲和力增强。
