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生物信息学方法鉴定达沙替尼和硼替佐米抑制 MCM7 蛋白的活性,作为一种潜在的人类癌症治疗方法。

Bioinformatics approaches identified dasatinib and bortezomib inhibit the activity of MCM7 protein as a potential treatment against human cancer.

机构信息

Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh.

Bioinformatics and Microbial Biotechnology Laboratory, Department of Genetic Engineering and Biotechnology, Jashore University of Science and Technology, Jashore, 7408, Bangladesh.

出版信息

Sci Rep. 2022 Jan 27;12(1):1539. doi: 10.1038/s41598-022-05621-0.


DOI:10.1038/s41598-022-05621-0
PMID:35087187
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8795118/
Abstract

Minichromosome Maintenance Complex Component 7 (MCM7) is a key component of the DNA replication licensing factor and hexamer MCM (MCM2-7) complex that regulates the DNA replication process. The MCM7 protein is associated with tumor cell proliferation that plays an important role in different human cancer progression. As the protein is highly expressed during the cancer development process, therefore, inhibition of the protein can be utilized as a treatment option for different human cancer. However, the study aimed to identify potential small molecular drug candidates against the MCM7 protein that can utilize treatment options for human cancer. Initially, the compounds identified from protein-drugs network analysis have been retrieved from NetworkAnalyst v3.0 server and screened through molecular docking, MM-GBSA, DFT, pharmacokinetics, toxicity, and molecular dynamics (MD) simulation approach. Two compounds namely Dasatinib (CID_3062316) and Bortezomib (CID_387447) have been identified throughout the screening process, which have the highest negative binding affinity (Kcal/mol) and binding free energy (Kcal/mol). The pharmacokinetics and toxicity analysis identified drug-like properties and no toxicity properties of the compounds, where 500 ns MD simulation confirmed structural stability of the two compounds to the targeted proteins. Therefore, we can conclude that the compounds dasatinib and bortezomib can inhibit the activity of the MCM7 and can be developed as a treatment option against human cancer.

摘要

微小染色体维持复合物成分 7(MCM7)是 DNA 复制许可因子和六聚体 MCM(MCM2-7)复合物的关键组成部分,该复合物调节 DNA 复制过程。MCM7 蛋白与肿瘤细胞增殖有关,在不同的人类癌症进展中起着重要作用。由于该蛋白在癌症发展过程中高度表达,因此,抑制该蛋白可以作为不同人类癌症的治疗选择。然而,本研究旨在鉴定针对 MCM7 蛋白的潜在小分子药物候选物,以利用人类癌症的治疗选择。最初,从蛋白质-药物网络分析中鉴定的化合物已从 NetworkAnalyst v3.0 服务器中检索出来,并通过分子对接、MM-GBSA、DFT、药代动力学、毒性和分子动力学(MD)模拟方法进行筛选。在筛选过程中鉴定了两种化合物,即达沙替尼(CID_3062316)和硼替佐米(CID_387447),它们具有最高的负结合亲和力(Kcal/mol)和结合自由能(Kcal/mol)。药代动力学和毒性分析确定了化合物具有类药性和无毒性特征,500ns MD 模拟证实了两种化合物对靶向蛋白的结构稳定性。因此,我们可以得出结论,化合物达沙替尼和硼替佐米可以抑制 MCM7 的活性,并可开发为针对人类癌症的治疗选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/8816f0679282/41598_2022_5621_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/f3943114fa1e/41598_2022_5621_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/14db6ab89e9b/41598_2022_5621_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/4d7f3660d051/41598_2022_5621_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/a120ce777314/41598_2022_5621_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/a06721bfa15e/41598_2022_5621_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/caeb8c375f84/41598_2022_5621_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/c79c89da66ac/41598_2022_5621_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/dd8edeb068db/41598_2022_5621_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/fee59460c1fe/41598_2022_5621_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/cc81da82dc98/41598_2022_5621_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/8816f0679282/41598_2022_5621_Fig11_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/f3943114fa1e/41598_2022_5621_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/14db6ab89e9b/41598_2022_5621_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/4d7f3660d051/41598_2022_5621_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/a120ce777314/41598_2022_5621_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/a06721bfa15e/41598_2022_5621_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/caeb8c375f84/41598_2022_5621_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/c79c89da66ac/41598_2022_5621_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/dd8edeb068db/41598_2022_5621_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/fee59460c1fe/41598_2022_5621_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/cc81da82dc98/41598_2022_5621_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/a05e/8795118/8816f0679282/41598_2022_5621_Fig11_HTML.jpg

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