Department of Chemistry, Wayne State University, 5101 Cass Avenue, Detroit, Michigan 48202, USA.
J Phys Chem B. 2010 Jan 21;114(2):1030-7. doi: 10.1021/jp909327y.
(4-Phenoxyphenylsulfonyl)methylthiirane (SB-3CT) is the selective inhibitor of matrix metalloproteinase 2 (MMP2). The inhibition mechanism of MMP2 by SB-3CT involves C-H deprotonation with concomitant opening of the three-membered heterocycle. In this study, the energetics of the deprotonation-induced ring-opening of (4-phenoxyphenylsulfinyl)methylthiirane, the sulfoxide analogue of SB-3CT, are examined computationally using DFT and QM/MM calculations. A model system, 2-(methylsulfinylmethyl)thiirane, is used to study the stereoelectronic and conformational effects of reaction barriers in methanol. For the model system in methanol solution (using the polarizable continuum model), the reaction barriers range from 17 to 23 kcal/mol with significant stereoelectronic effects. However, the lowest barriers of the (R,R) and (S,R) diastereomers are similar. Two diastereomers of the sulfoxide analogue of SB-3CT are studied in the active site of MMP2 by QM/MM methods with an accurate partial charge fitting procedure. The ring-opening reactions of these two diastereomers have similar reaction energetics. Both are exothermic from the reactant to the ring-opening product (thiolate). The protonation of the thiolate by a water molecule is endothermic in both cases. However, the deprotonation/ring-opening barriers in the MMP2 active site using QM/MM methods for the (R,R) and (S,R) inhibitions are quite different (23.3 and 28.5 kcal/mol, respectively). The TSs identified in QM/MM calculations were confirmed by vibrational frequency analysis and following the reaction path. The (R,R) diastereomer has a hydrogen bond between the sulfoxide oxygen and the backbone NH of Leu191, while the (S,R) has a hydrogen bond between the sulfoxide oxygen and a water molecule. The dissimilar strengths of these hydrogen bonds as well as minor differences in the TS structures contribute to the difference between the barriers. Compared to SB-3CT, both diastereomers of the sulfoxide analogue have higher reaction barriers and have less exothermic reaction energies. This agrees well with the experiments, where SB-3CT is a more effective inhibitor of MMP2 than its sulfoxide analogue.
（4-苯氧基苯基磺酰基）甲基硫杂环丙烷（SB-3CT）是基质金属蛋白酶2（MMP2）的选择性抑制剂。SB-3CT对MMP2的抑制机制涉及C-H去质子化并伴随三元杂环的开环。在本研究中，使用密度泛函理论（DFT）和量子力学/分子力学（QM/MM）计算方法对SB-3CT的亚砜类似物（4-苯氧基苯基亚磺酰基）甲基硫杂环丙烷去质子化诱导的开环能量进行了计算研究。使用模型体系2-（甲基亚磺酰基甲基）硫杂环丙烷来研究甲醇中反应势垒的立体电子效应和构象效应。对于甲醇溶液中的模型体系（使用极化连续介质模型），反应势垒范围为17至23千卡/摩尔，具有显著的立体电子效应。然而，（R,R）和（S,R）非对映异构体的最低势垒相似。通过QM/MM方法和精确的部分电荷拟合程序，在MMP2的活性位点研究了SB-3CT亚砜类似物的两种非对映异构体。这两种非对映异构体的开环反应具有相似的反应能量。从反应物到开环产物（硫醇盐）两者都是放热的。在两种情况下，水分子使硫醇盐质子化都是吸热的。然而，使用QM/MM方法在MMP2活性位点中（R,R）和（S,R）抑制的去质子化/开环势垒有很大差异（分别为23.3和28.5千卡/摩尔）。通过振动频率分析和跟踪反应路径，证实了QM/MM计算中确定的过渡态。（R,R）非对映异构体在亚砜氧和Leu191的主链NH之间存在氢键，而（S,R）在亚砜氧和一个水分子之间存在氢键。这些氢键强度的差异以及过渡态结构的微小差异导致了势垒之间的差异。与SB-3CT相比，亚砜类似物的两种非对映异构体都具有更高的反应势垒且反应能量的放热更少。这与实验结果非常吻合，在实验中SB-3CT是比其亚砜类似物更有效的MMP2抑制剂。
