QM/MM Studies of the Matrix Metalloproteinase 2 (MMP2) Inhibition Mechanism of (S)-SB-3CT and its Oxirane Analogue.
QM/MM Studies of the Matrix Metalloproteinase 2 (MMP2) Inhibition Mechanism of (S)-SB-3CT and its Oxirane Analogue.
复制标题
(S)-SB-3CT 及其 Oxirane 类似物的基质金属蛋白酶 2 (MMP2) 抑制机制的 QM/MM 研究。
DOI：
10.1021/ct100382k
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发表时间：
2010
影响因子：
5.5
通讯作者：
Schlegel,HBernhard
中科院分区：
文献类型：
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作者：
Zhou,Jia;Tao,Peng;Fisher,JedF;Shi,Qicun;Mobashery,Shahriar;Schlegel,HBernhard
SB-3CT, (4-phenoxyphenylsulfonyl)methylthiirane，是一种有效的，基于机制的锌蛋白酶基质金属蛋白酶（MMP）家族明胶酶亚类抑制剂。明胶酶MMPs是不寻常的，因为有几个例子，其中两个外消旋抑制剂的对映体具有相当的抑制能力。SB-3CT就是这样一个例子。本文通过计算研究了(S)-SB-3CT对映体及其氧环烷类似物对MMP2明胶酶的抑制机制，并与(R)-SB-3CT的抑制机制进行了比较。(R)-SB-3CT对MMP2的抑制作用先前被证明涉及酶催化的毗邻砜的C−H去质子化，伴随着β-消除三元硫环的硫而伴随的开放。与theRenantiomer类似，将(S)-SB-3CT对接到MMP2的活性位点，然后进行分子动力学模拟，制备配合物进行量子力学和分子力学（QM/MM）联合计算。QM/MM计算采用B3LYP/6-311+G（d,p）计算QM部分（46个原子）和AMBER力场计算（MM部分），比较(S)-SB-3CT及其氧环类似物在MMP2（9208个原子）活性位点上的反应。计算结果表明，(S)-SB-3CT在MMP2活性位点的质子抽离耦合开环反应势垒比类似物低4.4 kcal/mol，而(S)-SB-3CT的开环反应能仅比类似物低1.6 kcal/mol。计算还表明，水对开环产物的质子化对由氧环烷得到的醇盐比由硫环烷得到的硫酸盐要有利得多。与(R)-SB-3CT及其S-氧环类似物相比，(S)-SB-3CT及其S-氧环类似物的开环产物的双键具有顺式构型。在缩小尺寸QM/MM模型（2747个原子）上的振动频率和本征反应路径计算提供了对机理的进一步了解。计算结果表明，SB-3CT的两种对映体在过渡态C−H键劈裂的氘动力学同位素效应分别为5.9和6.7，与实验结果吻合较好。
SB-3CT, (4-phenoxyphenylsulfonyl)methylthiirane, is a potent, mechanism-based inhibitor of the gelatinase subclass of the matrix metalloproteinase (MMP) family of zinc proteases. The gelatinase MMPs are unusual in that there are several examples where both enantiomers of a racemic inhibitor have comparable inhibitory abilities. SB-3CT is one such example. Here, the inhibition mechanism of the MMP2 gelatinase by the (S)-SB-3CT enantiomer and its oxirane analogue is examined computationally and compared to the mechanism of (R)-SB-3CT. Inhibition of MMP2 by (R)-SB-3CT was shown previously to involve enzyme-catalyzed C−H deprotonation adjacent to the sulfone, with concomitant opening by β-elimination of the sulfur of the three-membered thiirane ring. Similarly to theRenantiomer, (S)-SB-3CT was docked into the active site of MMP2, followed by molecular dynamics simulation to prepare the complex for combined quantum mechanics and molecular mechanics (QM/MM) calculations. QM/MM calculations with B3LYP/6-311+G(d,p) for the QM part (46 atoms) and the AMBER force field for the MM part were used to compare the reaction of (S)-SB-3CT and its oxirane analogue in the active site of MMP2 (9208 atoms). These calculations show that the barrier for the proton abstraction coupled ring-opening reaction of (S)-SB-3CT in the MMP2 active site is 4.4 kcal/mol lower than that of its oxirane analogue, and the ring-opening reaction energy of (S)-SB-3CT is only 1.6 kcal/mol less exothermic than that of its oxirane analogue. Calculations also show that the protonation of the ring-opened products by water is thermodynamically much more favorable for the alkoxide obtained from the oxirane than for the thiolate obtained from the thiirane. In contrast to (R)-SB-3CT and theR-oxirane analogue, the double bonds of the ring-opened products of (S)-SB-3CT and itsS-oxirane analogue have the cis configuration. Vibrational frequency and intrinsic reaction path calculations on a reduced size QM/MM model (2747 atoms) provide additional insight into the mechanism. These calculations yield 5.9 and 6.7 for the deuterium kinetic isotope effect for C−H bond cleavage in the transition state for theRandSenantiomers of SB-3CT, in good agreement with the experimental results.
Y.Aoki.：Theochem。
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