细胞周期蛋白依赖性激酶6靶向药物再利用控制细胞增殖。

3区 生物学 Q1 Biochemistry, Genetics and Molecular Biology
N Madhana Priya, Ambritha Balasundaram, N Sidharth Kumar, S Udhaya Kumar, D Thirumal Kumar, R Magesh, Hatem Zayed, C George Priya Doss
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引用次数: 0

摘要

细胞周期蛋白依赖性激酶6 (CDK6)是细胞周期进程中必不可少的激酶,是包括乳腺癌在内的各种恶性肿瘤抑制剂的可行靶点。这项研究旨在虚拟筛选有效的化合物,作为使用药物再利用方法治疗乳腺癌的新线索。凋亡调节化合物取自seleckchem数据库。分子对接实验在abemaciclib的存在下进行,abemaciclib是FDA常用的药物。与传统药物相比,这两种化合物对CDK6具有更高的结合亲和力。化合物(n -苄基-6-[(4-羟基苯基)甲基]-8-(萘-1-基甲基)-4,7-二氧基-3,6,9,9a-四氢- 2h -吡嗪[1,2-a]嘧啶-1-羧酰胺)和(1'-[4-[1-(4-氟苯基)吲哚-3-基]丁基]螺[1h -2-苯并呋喃-3,4'-哌啶])对CDK6的抑制作用分别为-8.49和-6.78kcal/mol,而对照分子为-8.09kcal/mol。发现这两种新化合物的相互作用残基位于CDK6分子的结合位点内。与abemaciclib相比,这两种化合物具有相同的ADME特征,并且在适当的药物相似范围内分布良好并被人体代谢。最后,对选定的有效抑制剂和abemaciclib与CDK6络合的分子动力学进行了200ns的启动。通过RMSD、RMSF、Rg、氢键相互作用、SASA、PCA、FEL和MM/PBSA分析来评估配合物的稳定性、波动、旋转半径、氢键相互作用、溶剂可及性、基本动力学、自由能景观和MM/PBSA。所选的两种化合物都是小分子,在适当的药物相似范围内。分子对接和分子动力学模拟的结果表明,这两种化合物对CDK6具有较强的抑制作用。我们建议这些候选化合物可以进行体外验证和体内测试,以进一步用于抗癌。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Controlling cell proliferation by targeting cyclin-dependent kinase 6 using drug repurposing approach.

Cyclin-dependent kinase 6 (CDK6) is an essential kinase in cell cycle progression, which is a viable target for inhibitors in various malignancies, including breast cancer. This study aimed to virtually screen efficient compounds as new leads in treating breast cancer using a drug repurposing approach. Apoptosis regulatory compounds were taken from the seleckchem database. Molecular docking experiments were carried out in the presence of abemaciclib, a routinely used FDA drug. Compared to conventional drugs, the two compounds demonstrated a higher binding affinity for CDK6. Compounds (N-benzyl-6-[(4-hydroxyphenyl)methyl]-8-(naphthalen-1-ylmethyl)-4,7-dioxo-3,6,9,9a-tetrahydro-2H-pyrazino[1,2-a]pyrimidine-1-carboxamide) and (1'-[4-[1-(4-fluorophenyl)indol-3-yl]butyl]spiro[1H-2-benzofuran-3,4'-piperidine]) were discovered to have an inhibitory effect against CDK6 at -8.49 and -6.78kcal/mol, respectively, compared to -8.09kcal/mol of the control molecule, the interacting residues of these two new compounds were found to fall within the binding site of the CDK6 molecule. Both compounds exhibited equal ADME features compared with abemaciclib and would be well distributed and metabolized by the body with an appropriate druglikeness range. Lastly, molecular dynamics was initiated for 200ns for the selected potent inhibitors and abemaciclib as complexed with CDK6. The RMSD, RMSF, Rg, H-Bond interactions, SASA, PCA, FEL, and MM/PBSA analysis were performed for the complexes to assess the stability, fluctuations, radius of gyration, hydrogen bond interaction, solvent accessibility, essential dynamics, free energy landscape, and MM/PBSA. The selected two compounds are small molecules in the appropriate druglikeness range. The results observed in molecular docking and molecular dynamics simulations were most promising for two compounds, suggesting their potent inhibitory effect against CDK6. We propose that these candidate compounds can undergo in vitro validation and in vivo testing for their further use against cancer.

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来源期刊
Advances in protein chemistry and structural biology
Advances in protein chemistry and structural biology BIOCHEMISTRY & MOLECULAR BIOLOGY-
CiteScore
7.40
自引率
0.00%
发文量
66
审稿时长
>12 weeks
期刊介绍: Published continuously since 1944, The Advances in Protein Chemistry and Structural Biology series has been the essential resource for protein chemists. Each volume brings forth new information about protocols and analysis of proteins. Each thematically organized volume is guest edited by leading experts in a broad range of protein-related topics.
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