Impact of mobility on structure-based drug design for the MMPs
Impact of mobility on structure-based drug design for the MMPs
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DOI：
10.1021/ja027391x
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发表时间：
2002-10-30
影响因子：
15
通讯作者：
Powers, R
中科院分区：
文献类型：
--
作者：
Moy, FJ;Chanda, PK;Powers, R
由于实践的限制，基于结构的药物设计方法一般不包括溶剂效应和动态信息来预测抑制剂结合亲和力。基质金属蛋白酶(MMPs)已被证明在其活性部位表现出显著的流动性。这种动态特性使基于静态结构的药物设计过程显著复杂化，这在一类含有丁炔基官能团的异羟肟酸中得到了明显的观察。根据预测的丁炔基P1‘基团和S1’口袋之间的空间碰撞，预计化合物1对MMP-1具有选择性，但对MMP-1：1核磁共振结构中复杂抑制剂动力学的观察为低纳米分子与基质金属蛋白酶-1的结合提供了解释。
Structure-based approaches for drug design generally do not incorporate solvent effects and dynamic information to predict inhibitor-binding affinity because of practical limitations. The matrix metalloproteinases (MMPs) have previously been demonstrated to exhibit significant mobility in their active sites. This dynamic characteristic significantly complicates the drug design process based on static structures, which was clearly observed for a class of hydroxamic acids containing a butynyl moiety. Compound1was expected to be selective against MMP-1 based on predicted steric clashes between the butynyl P1‘ group and the S1‘ pocket, but the observation of complex inhibitor dynamics in the NMR structure of MMP-1:1provides an explanation for the low nanomolar binding to MMP-1.