Structure-based design of a novel, potent, and selective inhibitor for MMP-13 utilizing NMR spectroscopy and computer-aided molecular design
Structure-based design of a novel, potent, and selective inhibitor for MMP-13 utilizing NMR spectroscopy and computer-aided molecular design
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DOI：
10.1021/ja001547g
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发表时间：
2000-10-11
影响因子：
15
通讯作者：
Powers, R
中科院分区：
文献类型：
--
作者：
Chen, JM;Nelson, FC;Powers, R
以人胶原酶-3催化片段(MMP13)的高分辨核磁共振溶液结构为起点，进行了MMP13选择性抑制剂的结构设计。观察到的基质金属蛋白酶结构之间的主要结构差异是S1‘口袋的相对大小和形状，其中对于基质金属蛋白酶-13来说，这个口袋明显更长，几乎到达蛋白质的表面。基于基质金属蛋白酶-13 S1‘口袋的扩展性质，从最初的高通量筛选(HTS)引线设计了一种对基质金属蛋白酶-13有效和选择性的抑制剂。CL-82198对基质金属蛋白酶-13的抑制作用较弱(10微米)，而对基质金属蛋白酶-1、基质金属蛋白酶-9或相关的血管紧张素转换酶无活性。CL-82198的类药物性质使其成为优化酶效力和选择性的理想候选者。核磁共振结合研究表明，抑制剂CL-82198结合在基质金属蛋白酶-13的整个S1‘口袋内，这是其对基质金属蛋白酶-1、基质金属蛋白酶-9和血管紧张素转换酶的选择性的基础。利用这一信息设计了一种策略，用于设计对基质金属蛋白酶-13具有更强选择性的新抑制剂。我们的设计策略结合了CL-82198的关键选择性特征和非特异性基质金属蛋白酶抑制剂(WAY-152177)的已知效力特征，以产生有效和选择性的基质金属蛋白酶-13抑制剂(WAY-170523)。Way-170523对基质金属蛋白酶-13的IC_(50)为17 nM，对基质金属基质金属蛋白酶-1、基质金属蛋白酶-9和化疗药物血管紧张素转换酶的选择性分别为5800、56和500倍。
The high-resolution NMR solution structure of the catalytic fragment of human collagenase-3 (MMP-13) was used as a starting point for structure-based design of selective inhibitors for MMP-13. The major structural difference observed between the MMP structures is the relative size and shape of the S1' pocket where this pocket is significantly longer for MMP-13, nearly reaching the surface of the protein. On the basis of the extended nature of the MMP-13 S1' pocket an inhibitor potent and selective for MMP-13 was designed from an initial high throughput screening (HTS) lead. CL-82198 was identified as a weak (10 muM) inhibitor against MMP-13 while demonstrating no activity against MMP-1, MMP-9, or the related enzyme TACE. The drug-Like properties of CL-82198 made it an ideal candidate for optimization of enzyme potency and selectivity. On the basis of NMR binding studies, it was shown that inhibitor CL-82198 bound within the entire S1' pocket of MMP-13 which is the basis of its selectivity against MMP-1, MMP-9, and TACE. A strategy utilizing this information was devised for designing new inhibitors that showed enhanced selectivity toward MMP-13. Our design strategy combined the critical selectivity features of CL-82198 with the known potency features of a nonspecific MMP inhibitor (WAY-152177) to generate a potent and selective MMP-13 inhibitor (WAY-170523). WAY-170523 has an IC50 of 17 nM for MMP-13 and showed > 5800-, 56-, and >500-fold selectivity against MMP-1 MMP-9, and TACE, respectively.