Thompson S K, Smith W W, Zhao B, Halbert S M, Tomaszek T A, Tew D G, Levy M A, Janson C A, DAlessio K J, McQueney M S, Kurdyla J, Jones C S, DesJarlais R L, Abdel-Meguid S S, Veber D F
Departments of Medicinal Chemistry, Structural Biology, Molecular Recognition, Protein Biochemistry, and Physical and Structural Chemistry, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania 19406, USA.
J Med Chem. 1998 Oct 8;41(21):3923-7. doi: 10.1021/jm980474x.
Peptidomimetic cathepsin K inhibitors have been designed using binding models which were based on the X-ray crystal structure of an amino acid-based, active site-spanning inhibitor complexed with cathepsin K. These inhibitors, which contain a benzyloxybenzoyl group in place of a Cbz-leucine moiety, maintained good inhibitory potency relative to the amino acid-based inhibitor, and the binding models were found to be very predictive of relative inhibitor potency. The binding mode of one of the inhibitors was confirmed by X-ray crystallography, and the crystallographically determined structure is in close qualitative agreement with the initial binding model. These results strengthen the validity of a strategy involving iterative cycles of structure-based design, inhibitor synthesis and evaluation, and crystallographic structure determination for the discovery of peptidomimetic inhibitors.
基于与组织蛋白酶K复合的氨基酸基活性位点跨域抑制剂的X射线晶体结构构建结合模型，设计出了拟肽类组织蛋白酶K抑制剂。这些抑制剂含有苄氧基苯甲酰基取代Cbz-亮氨酸部分，相对于氨基酸基抑制剂保持了良好的抑制效力，并且发现结合模型对相对抑制剂效力具有很强的预测性。通过X射线晶体学证实了其中一种抑制剂的结合模式，晶体学确定的结构与初始结合模型在定性上非常吻合。这些结果加强了一种策略的有效性，该策略包括基于结构的设计、抑制剂合成与评估以及晶体结构测定的迭代循环，用于发现拟肽类抑制剂。
