Matrix metalloproteinase inhibitors: A structure-activity study
Matrix metalloproteinase inhibitors: A structure-activity study
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DOI：
10.1021/jm970494j
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发表时间：
1998-01-15
影响因子：
7.3
通讯作者：
Galardy, RE
中科院分区：
文献类型：
--
作者：
Levy, DE;Lapierre, F;Galardy, RE
研究了一种羟肟酸基基质金属蛋白酶抑制剂的二肽模拟核心修饰。除了P1‘和P3’取代基的修饰外，这些变体还包含了各种天然的、非天然的和合成的氨基酸。本研究结果表明了以下结构要求：(1)酶和有效底物之间必须存在两个关键的氢键。(2)有效抑制剂必须具有很强的锌结合功能。(3)当使用较大的疏水基团时，R3位置的疏水基团具有更大的抗基质溶素的相对效力，这说明了它的潜在重要性。(4)与中性粒细胞胶原酶、72 kDa明胶酶和92 kDa明胶酶相比，基质溶解素对氨基酸性质的要求似乎更严格。这些要求可能涉及平面环芳基体系和可能的氢键能力。
Modifications around the dipeptide-mimetic core of a hydroxamic acid based matrix metalloproteinase inhibitor were studied. These variations incorporated a variety of natural, unnatural, and synthetic amino acids in addition to modifications of the P1' and P3' substituents. The results of this study indicate the following structural requirements: (1) Two key hydrogen bonds must be present between the enzyme and potent substrates. (2) Potent inhibitors must possess strong zinc-binding functionalities. (3) The potential importance of the hydrophobic group at position R3 as illustrated by its ability to impart greater relative potency against stromelysin when larger hydrophobic groups are used. (4) Requirements surrounding the nature of the amino acid appear to be more restrictive for stromelysin than for neutrophil collagenase, 72 kDa gelatinase, and 92 kDa gelatinase. These requirements may involve planar fused-ring aryl systems and possibly hydrogen-bonding capabilities.