Identification of Sulfamoylbenzamide derivatives as selective Cathepsin D inhibitors.
Identification of Sulfamoylbenzamide derivatives as selective Cathepsin D inhibitors.
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发表时间：
2013-07
影响因子：
0.8
通讯作者：
Waseem Ahmed;I. Khan;M. Arshad;W. Siddiqui;M. A. Haleem;M. Azim
中科院分区：
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作者：
Waseem Ahmed;I. Khan;M. Arshad;W. Siddiqui;M. A. Haleem;M. Azim
天冬氨酸蛋白酶在蛋白质翻译后加工中起着非常重要的作用，其中一些蛋白酶对生物体的生存至关重要。在这里，我们提出了不同的氨磺酰苯甲酰胺衍生物对两个天冬氨酸蛋白酶组织蛋白酶D和plasmepsin II的酶抑制活性。组织蛋白酶D是一种天冬氨酸蛋白酶，在酸性pH下降解溶酶体或细胞外基质中的蛋白质。它被乳腺癌上皮细胞过度表达，因此过度分泌。另一方面，plasmepsin II是恶性疟原虫的必需酶。组织蛋白酶D和Plasmepsin II分别是治疗乳腺癌和疟疾的关键药物靶标。氨磺酰苯甲酰胺化合物的虚拟筛选，随后进行酶抑制测定，揭示了这些化合物作为选择性组织蛋白酶D抑制剂，而对Plasmepsin-II无活性。检测的5种氨磺酰苯甲酰胺化合物的IC 50值在1.25-2.0 μM范围内。N-（3-氯苯基）-2-氨磺酰基苯甲酰胺被确定为所有检测的氨磺酰基苯甲酰胺化合物中最有效的，IC 50为1.25 μM。还注意到，与Plasmepsin-II相比，在组织蛋白酶D的情况下，这些化合物的对接评分更好。组织蛋白酶D的对接评分范围为-29.9 ~1.16至-35.1 ~0.13，而Plasmepsin-II的为-24.0 ~0.10至-29.5 ~0.10。
Aspartic proteases play very important role in post translational processing of proteins and several of them are essential for organism's viability. Here we present the enzyme inhibition activities of different Sulfamoylbenzamide derivatives against two aspartic proteases cathepsin D and plasmepsin II. Cathepsin D is an aspartic protease that degrades proteins at acidic pH in the lysosomes, or extracellular matrix. It is overexpressed by epithelial breast cancer cells and hence hyper-secreted. On the other hand plasmepsin II is an essential enzyme of Plasmodium falciperum. Cathepsin D and Plasmepsin II are pivotal drug targets for treatment of breast cancer and malaria respectively. Virtual screening of Sulfamoylbenzamide compounds followed by enzyme inhibition assays revealed these compounds as selective Cathepsin D inhibitors while inactive against Plasmepsin-II. IC50 values of five Sulfamoylbenzamide compounds tested are in range of 1.25-2.0 μM. N-(3-chlorophenyl)-2-sulfamoylbenzamide is identified as the most potent of all tested Sulfamoylbenzamide compounds with IC50 1.25 μM. It was also noted that the docking score of theses compounds was better in case of Cathepsin D as compared to Plasmepsin-II. Docking score ranges from -29.9±1.16 to -35.1±0.13 in case of Cathepsin D, while from -24.0±0.10 to -29.5±0.10 in case of Plasmepsin-II.