Highly selective aza-nitrile inhibitors for cathepsin K, structural optimization and molecular modeling.
Highly selective aza-nitrile inhibitors for cathepsin K, structural optimization and molecular modeling.
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DOI：
10.1039/c3ob41165f
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发表时间：
2013-08
影响因子：
3.2
通讯作者：
X. Yuan;Dingyi Fu;Xing-Feng Ren;Xuexun Fang;Lincong Wang;Shuxue Zou;Yuqing Wu
中科院分区：
文献类型：
--
作者：
X. Yuan;Dingyi Fu;Xing-Feng Ren;Xuexun Fang;Lincong Wang;Shuxue Zou;Yuqing Wu
氮杂二肽腈类化合物作为一种新型的组织蛋白酶K抑制剂，具有蛋白水解稳定性好、抑制活性高等特点，但选择性较差。人们一直致力于提高它们对组织蛋白酶K的选择性。在这个连续的研究中，我们报告了进一步的结构优化，合成，分子建模，并在体外酶活性测定的一系列新的有效的和选择性的组织蛋白酶K抑制剂没有P2-P3酰胺接头。相对于L、S和B，组织蛋白酶K实现了显著的选择性改善，并且三芳基间位产物具有组织蛋白酶K的效力（Ki = 0.29 nM）和选择性之间的有利平衡，相对于组织蛋白酶L（320倍）、S（1784倍）和B（8566倍）。我们进行了共价蛋白质配体对接研究，以解释几个代表性化合物的选择性提高。这样的选择性改进将有助于避免这些化合物在实际应用中的有害副作用。
As a new type of cathepsin K inhibitor, azadipeptide nitriles have the characteristics of proteolytic stability and excellent inhibitory activity, but they exhibit barely any satisfactory selectivity. Great efforts have focused on improving their selectivity toward cathepsin K. In this sequential study, we report the further structural optimization, synthesis, molecular modeling, and in vitro enzymatic assays of a new series of potent and selective inhibitors of cathepsin K without the P2-P3 amide linker. Significant selective improvements were achieved for cathepsin K over L, S and B, and a triaryl meta-product possessed the favorable balance between potency (Ki = 0.29 nM) and selectivity of cathepsin K over cathepsin L (320-fold), S (1784-fold) and B (8566-fold). We undertook a covalent protein-ligand docking study to explain the improved selectivity of several representative compounds. Such a selectivity improvement would be useful to avoid harmful side effects in practical applications of these compounds.