A theoretical study of the molecular mechanism of the GAPDH Trypanosoma cruzi enzyme involving iodoacetate inhibitor
A theoretical study of the molecular mechanism of the GAPDH Trypanosoma cruzi enzyme involving iodoacetate inhibitor
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DOI：
10.1016/j.cplett.2011.08.051
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发表时间：
2011-10-06
影响因子：
2.8
通讯作者：
Alves, Claudio Nahum
中科院分区：
文献类型：
--
作者：
Carneiro, Agnaldo Silva;Lameira, Jeronimo;Alves, Claudio Nahum
甘油醛-3-磷酸脱氢酶（GAPDH）是开发抗恰加斯病新化疗药物的重要生物学靶标。本文采用混合量子力学/分子力学（QM/MM）方法和分子动力学模拟研究了碘乙酸（IAA）抑制剂对GAPDH的抑制机理。势能面和平均力势的分析表明，IAA抑制剂与酶活性位点的共价结合是一个协同过程。能量项分解结果表明，NAD+对反应物和过渡态的稳定起重要作用。(C)2011年爱思唯尔B。V.保留所有权利。
The glyceraldehyde-3-phosphate dehydrogenase enzyme (GAPDH) is an important biological target for the development of new chemotherapeutic agents against Chagas disease. In this Letter, the inhibition mechanism of GAPDH involving iodoacetate (IAA) inhibitor was studied using the hybrid quantum mechanical/molecular mechanical (QM/MM) approach and molecular dynamic simulations. Analysis of the potential energy surface and potential of mean force show that the covalent attachment of IAA inhibitor to the active site of the enzyme occurs as a concerted process. In addition, the energy terms decomposition shows that NAD+ plays an important role in stabilization of the reagents and transition state. (C) 2011 Elsevier B. V. All rights reserved.