基质金属蛋白酶抑制剂的效能和选择性以及查尔酮合酶的催化反应机理的理论研究
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摘要
本文利用分子力学、分子动力学和量子力学方法,对基质金属蛋白酶(MMPs)的一类新型抑制剂的效能和选择性,以及查尔酮合酶(CHS)的催化反应机理进行了理论研究。主要结果如下:
1.通过分子力学和分子动力学方法,对基质金属蛋白酶家族的两个成员(MMP-1和MMP-3)与一类新型抑制剂(Pyrogallic acid和Myricetin)进行了分子对接研究,分别考察了两个抑制剂与MMPs的结合方式,从而阐明了Pyrogallic acid和Myricetin在效能和选择性上产生差异的原因。此外,量子化学计算结果显示此类抑制剂的锌结合基团以单配位形式与MMPs中有催化活性的Zn2+相结合。
2.通过分子力学和分子动力学方法,对基质金属蛋白酶家族的另外两个成员(MMP-2和MMP-9)与新型抑制剂(Myricetin和Kaempferol)进行了分子对接研究,分别考察了两个抑制剂与MMPs的结合方式,并在此基础上阐明了Myricetin和Kaempferol在效能和选择性上产生差异的原因。量子化学计算结果再次显示此类抑制剂的锌结合基团以单配位形式与MMPs中有催化活性的Zn2+相结合。
3.通过分子力学、分子动力学和量子力学方法,研究了经查尔酮合酶(CHS)催化,由P-coumaroyl-CoA和Malonyl-CoA合成查尔酮(Chalcone)的反应机理。结果显示:在加载步骤(Loading step)的反应路径中不存在过渡态,反应仅经过一个中间体到达产物;在脱羧步骤中(Decarboxylation step),反应要经过一个过渡态到达产物,并且该步反应对环境很敏感;在链延长步骤中(Elongation step),反应仍然要经过一个过渡态到达产物。理论计算的结果很好的支持并完善了实验上提出的反应机理。
In recent years, along with the development of molecule mechanics, dynamics, and quantum mechanics theories, and the progress of calculator technique, molecule simulations have already become a main research method in the fields of biology and medical science to analyze the interactions between receptor and ligand, and describe protein biochemistry mechanism.
In our thesis, molecule mechanics, dynamics, and quantum mechanics methods were used to theoretically study the potency and selectivity of matrix metalloproteinases (MMPs) inhibitors and the reaction mechanism catalyzed by chalcone synthase (CHS). The main results are summarized as follows:
1. Theoretical studies on potency and selectivity of novel non-peptide inhibitors of MMP-1 and MMP-3
To investigate the binding modes between the novel non-peptide inhibitors (Pyrogallic acid and Myricetin) and MMPs (MMP-1 and MMP-3), molecular docking studies were performed. The results indicate that Myricetin is more potent than Pyrogallic acid due to the P1’group at C13 atom of Myricetin, which interacts with S1’pocket of MMPs and thus contributes a lot to the binding affinity. The reasons for that Myricetin is more selective towards MMP-1 than MMP-3 may include the positions of zinc binding group (ZBG), the number of hydrogen bonds, and the interactions between P1’and S1’. Furthermore, the hydroxyl acts as a relatively weak ZBG and the meta-double-hydroxyl mode may be conserved when inhibitors of this kind bind to MMPs. Quantum chemistry calculation results show that inhibitors can bind to the catalytic zinc ion of MMPs with ZBG in a monodentate way.
2. Theoretical studies on potency and selectivity of novel non-peptide inhibitors of MMP-2 and MMP-9
Molecular docking studies were performed to investigate the binding modes between the novel non-peptide inhibitors (Myricetin and Kaempferol) and MMPs (MMP-2 and MMP-9). The results indicate that the completely different binding modes, resulting from that Myricetin owns two more side hydroxyls on benzene ring, lead to that Myricetin is more potent than Kaempferol; in aspect of selectivity, the similar binding modes in each complex pair (m-MMP2 and m-MMP9, k-MMP2 and k-MMP9) make the non-obvious selectivities of inhibitors. Moreover, the hydroxyl acts as a relatively weak ZBG and the meta-double-hydroxyl mode may be conserved. Quantum chemistry calculation results show again that inhibitors can bind to the catalytic zinc ion of MMPs with ZBG in a monodentate way.
3. Theoretical studies on the reaction mechanism catalyzed by CHS
The chalcone formation catalyzed by CHS from P-coumaroyl-CoA and Malonyl-CoA were theoretically studied. The calculation results indicate that in loading step, the reaction proceeds via a tetrahedral intermediate without transition state (TS); in decarboxylation step, the reaction proceeds via a TS and is sensitive to the environment; in elongation step, the reaction proceeds via a tetrahedral TS. The calculation results greatly support and complement the reaction mechanism proposed on experiment.
1.通过分子力学和分子动力学方法,对基质金属蛋白酶家族的两个成员(MMP-1和MMP-3)与一类新型抑制剂(Pyrogallic acid和Myricetin)进行了分子对接研究,分别考察了两个抑制剂与MMPs的结合方式,从而阐明了Pyrogallic acid和Myricetin在效能和选择性上产生差异的原因。此外,量子化学计算结果显示此类抑制剂的锌结合基团以单配位形式与MMPs中有催化活性的Zn2+相结合。
2.通过分子力学和分子动力学方法,对基质金属蛋白酶家族的另外两个成员(MMP-2和MMP-9)与新型抑制剂(Myricetin和Kaempferol)进行了分子对接研究,分别考察了两个抑制剂与MMPs的结合方式,并在此基础上阐明了Myricetin和Kaempferol在效能和选择性上产生差异的原因。量子化学计算结果再次显示此类抑制剂的锌结合基团以单配位形式与MMPs中有催化活性的Zn2+相结合。
3.通过分子力学、分子动力学和量子力学方法,研究了经查尔酮合酶(CHS)催化,由P-coumaroyl-CoA和Malonyl-CoA合成查尔酮(Chalcone)的反应机理。结果显示:在加载步骤(Loading step)的反应路径中不存在过渡态,反应仅经过一个中间体到达产物;在脱羧步骤中(Decarboxylation step),反应要经过一个过渡态到达产物,并且该步反应对环境很敏感;在链延长步骤中(Elongation step),反应仍然要经过一个过渡态到达产物。理论计算的结果很好的支持并完善了实验上提出的反应机理。
In recent years, along with the development of molecule mechanics, dynamics, and quantum mechanics theories, and the progress of calculator technique, molecule simulations have already become a main research method in the fields of biology and medical science to analyze the interactions between receptor and ligand, and describe protein biochemistry mechanism.
In our thesis, molecule mechanics, dynamics, and quantum mechanics methods were used to theoretically study the potency and selectivity of matrix metalloproteinases (MMPs) inhibitors and the reaction mechanism catalyzed by chalcone synthase (CHS). The main results are summarized as follows:
1. Theoretical studies on potency and selectivity of novel non-peptide inhibitors of MMP-1 and MMP-3
To investigate the binding modes between the novel non-peptide inhibitors (Pyrogallic acid and Myricetin) and MMPs (MMP-1 and MMP-3), molecular docking studies were performed. The results indicate that Myricetin is more potent than Pyrogallic acid due to the P1’group at C13 atom of Myricetin, which interacts with S1’pocket of MMPs and thus contributes a lot to the binding affinity. The reasons for that Myricetin is more selective towards MMP-1 than MMP-3 may include the positions of zinc binding group (ZBG), the number of hydrogen bonds, and the interactions between P1’and S1’. Furthermore, the hydroxyl acts as a relatively weak ZBG and the meta-double-hydroxyl mode may be conserved when inhibitors of this kind bind to MMPs. Quantum chemistry calculation results show that inhibitors can bind to the catalytic zinc ion of MMPs with ZBG in a monodentate way.
2. Theoretical studies on potency and selectivity of novel non-peptide inhibitors of MMP-2 and MMP-9
Molecular docking studies were performed to investigate the binding modes between the novel non-peptide inhibitors (Myricetin and Kaempferol) and MMPs (MMP-2 and MMP-9). The results indicate that the completely different binding modes, resulting from that Myricetin owns two more side hydroxyls on benzene ring, lead to that Myricetin is more potent than Kaempferol; in aspect of selectivity, the similar binding modes in each complex pair (m-MMP2 and m-MMP9, k-MMP2 and k-MMP9) make the non-obvious selectivities of inhibitors. Moreover, the hydroxyl acts as a relatively weak ZBG and the meta-double-hydroxyl mode may be conserved. Quantum chemistry calculation results show again that inhibitors can bind to the catalytic zinc ion of MMPs with ZBG in a monodentate way.
3. Theoretical studies on the reaction mechanism catalyzed by CHS
The chalcone formation catalyzed by CHS from P-coumaroyl-CoA and Malonyl-CoA were theoretically studied. The calculation results indicate that in loading step, the reaction proceeds via a tetrahedral intermediate without transition state (TS); in decarboxylation step, the reaction proceeds via a TS and is sensitive to the environment; in elongation step, the reaction proceeds via a tetrahedral TS. The calculation results greatly support and complement the reaction mechanism proposed on experiment.
引文
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