Coralyne Targets the Catalytic Domain of MMP9: An In Silico and In Vitro Investigation.

Q4 Biochemistry, Genetics and Molecular Biology
Rahul Kumar Vempati, Rama Rao Malla
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引用次数: 0

Abstract

Coralyne (COR) is a protoberberine-like isoquinoline alkaloid, and it is known for double-stranded (ds) DNA intercalation and topoisomerase inhibition. It can also sensitize cancer cells through various mechanisms. COR reduces the proliferation and migration of breast cancer cells by inhibiting the expression and activity of matrix metalloproteinase 9 (MMP9). However, the mechanism involved in the inhibitory activity of COR on MMP9 is not known. In the present study, in silico docking studies showed that COR binds to the active site of MMP9 catalytic domain (MMP9-CD) with considerable affinity. The binding affinity of COR to the MMP9-CD, estimated by three different web servers: CB Dock, Seam Dock, and PyRx, was found to be either -7.4 or -7.5 kcal/mol. Another web server that is routinely used for docking studies, Docking Server, has predicted a binding affinity of -5.9 kcal/mol. All four docking servers predicted the same binding site for COR within the MMP9-CD. Corroborating our docking results, molecular dynamic simulation studies have also shown that COR interacts with the same key active site amino acid residues of the MMP9-CD that are essential for its proteolytic function. Molecular mechanics with generalized born and surface area (MMGBSA) calculations using Schrodinger's prime module have shown that the binding free energy with which COR binds to MMP9 is -50 kcal/mol. It inhibited activity of recombinant human MMP9 activity and induced significant cytotoxicity and reduced the proliferation of MDA-MB 468 cells. Overall, our in silico and in vitro experiments show that COR potentially inhibits the activity of MMP9 by directly binding to the active site of its catalytic domain and possibly inhibits proliferation of MDA-MB 468 cells.

Coralyne靶向MMP9的催化结构域:一个硅和体外研究。
Coralyne (COR)是一种类似于原小檗碱的异喹啉类生物碱,具有嵌入双链DNA和抑制拓扑异构酶的功能。它还可以通过各种机制使癌细胞敏感。COR通过抑制基质金属蛋白酶9 (matrix metalloproteinase 9, MMP9)的表达和活性,减少乳腺癌细胞的增殖和迁移。然而,COR对MMP9的抑制作用机制尚不清楚。在本研究中,硅对接研究表明,COR以相当的亲和力结合到MMP9催化结构域的活性位点(MMP9- cd)。通过三个不同的web服务器:CB Dock、Seam Dock和PyRx估计,COR与MMP9-CD的结合亲和力为-7.4或-7.5 kcal/mol。另一个经常用于对接研究的web服务器,对接服务器,已经预测了-5.9 kcal/mol的结合亲和力。所有四个对接服务器都预测了MMP9-CD中COR的相同结合位点。分子动力学模拟研究也证实了我们的对接结果,表明COR与MMP9-CD的相同关键活性位点氨基酸残基相互作用,这些氨基酸残基对其蛋白水解功能至关重要。利用薛定谔素数模进行广义出生和表面积(MMGBSA)计算的分子力学结果表明,COR与MMP9的结合自由能为-50 kcal/mol。抑制重组人MMP9活性,诱导显著的细胞毒性,降低MDA-MB 468细胞的增殖。总之,我们的硅和体外实验表明,COR可能通过直接结合MMP9催化结构域的活性位点抑制MMP9的活性,并可能抑制MDA-MB 468细胞的增殖。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Critical Reviews in Oncogenesis
Critical Reviews in Oncogenesis Biochemistry, Genetics and Molecular Biology-Cancer Research
CiteScore
1.70
自引率
0.00%
发文量
17
期刊介绍: The journal is dedicated to extensive reviews, minireviews, and special theme issues on topics of current interest in basic and patient-oriented cancer research. The study of systems biology of cancer with its potential for molecular level diagnostics and treatment implies competence across the sciences and an increasing necessity for cancer researchers to understand both the technology and medicine. The journal allows readers to adapt a better understanding of various fields of molecular oncology. We welcome articles on basic biological mechanisms relevant to cancer such as DNA repair, cell cycle, apoptosis, angiogenesis, tumor immunology, etc.
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