Borišek Jure, Vizovišek Matej, Sosnowski Piotr, Turk Boris, Turk Dušan, Mohar Barbara, Novič Marjana
National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
Department of Biochemistry, Molecular and Structural Biology, Jozef Stefan Institute , Jamova cesta 39, SI-1000 Ljubljana, Slovenia.
J Med Chem. 2015 Sep 10;58(17):6928-37. doi: 10.1021/acs.jmedchem.5b00746. Epub 2015 Aug 26.
Cathepsin K is a major drug target for osteoporosis and related-bone disorders. Using a combination of virtual combinatorial chemistry, QSAR modeling, and molecular docking studies, a series of cathepsin K inhibitors based on N-(functionalized benzoyl)-homocycloleucyl-glycinonitrile scaffold was developed. In order to avoid previous problems of cathepsin K inhibitors associated with lysosomotropism of compounds with basic character that resulted in off-target effects, a weakly- to nonbasic moiety was incorporated into the P3 position. Compounds 5, 6, and 9 were highly selective for cathepsin K when compared with cathepsins L and S, with the Ki values in the 10-30 nM range. The kinetic studies revealed that the new compounds exhibited reversible tight binding to cathepsin K, while the X-ray structural studies showed covalent and noncovalent binding between the nitrile group and the catalytic cysteine (Cys25) site.
组织蛋白酶K是骨质疏松症及相关骨疾病的主要药物靶点。通过虚拟组合化学、定量构效关系（QSAR）建模和分子对接研究相结合的方法，开发了一系列基于N-（官能化苯甲酰基）-高环亮氨酰-甘氨腈支架的组织蛋白酶K抑制剂。为了避免先前组织蛋白酶K抑制剂存在的问题，即具有碱性特征的化合物的溶酶体趋向性会导致脱靶效应，在P3位引入了弱碱性至非碱性部分。与组织蛋白酶L和S相比，化合物5、6和9对组织蛋白酶K具有高度选择性，其抑制常数（Ki）值在纳摩尔范围内。动力学研究表明，新化合物与组织蛋白酶K表现出可逆的紧密结合，而X射线结构研究表明腈基与催化性半胱氨酸（Cys25）位点之间存在共价和非共价结合。
