利用天然化合物对乳腺癌患者的 DNA 修复 MRN-检查点感应基因（MRN-CSGs）和致癌 miRNAs 进行多靶点治疗调节：一项临床信息研究。

IF 1.5 4区生物学 Q4 CELL BIOLOGY

Integrative Biology Pub Date : 2024-01-23 DOI:10.1093/intbio/zyae019

Jitender Singh, Krishan L Khanduja, Pramod K Avti

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引用次数: 0

摘要

乳腺癌在女性中发病率较高，通常是由于负责 DNA 损伤检测和修复的 MRN-检查点传感器基因（MRN-CSG）异常所致。这一复合体的异常会抑制各种效应因子，如 siRNA、miRNA 和转录因子，从而导致乳腺肿瘤的进展。本研究分析了乳腺肿瘤样本（n = 60），从12个miRNA中鉴定出了4个常见的miRNA（miR-1-3p、miR-210-3p、miR-16-5p、miR-34a-5p），并探讨了它们与MRN-CSG的相互作用。这些 miRNA-MRN-CSG 复合物的三维结构显示出很强的热力学稳定性。对 7711 种天然化合物进行筛选后，发现两种天然化合物（F0870-0001 和 F0922-0471）的配体结合能最低（ΔG = -8.4 至 11.6 kcal/mol），可靶向两种常见的 miRNA。对接结果显示，一种天然化合物（PubChem id-5 281 614）与所有 MRN-CSG 成分结合（ΔG = -6.2 至 -7.3 kcal/mol），而 F6782-0723 只与 RAD50 和 NBN 结合。这些化合物表现出最小解离常数（Kd 和 Ki）和热力学稳定的最小自由能（MMGBSA）值。分子动力学模拟表明，天然化合物-MRN-CSG 复合物高度稳定，具有一致的 RMSD、RMSF 和较强的残差相关性。这些经过严格筛选的化合物显示出强大的分子间 H 键、低致癌性、低毒性和类药物特性。因此，这些化合物有望在乳腺癌治疗中调节 miRNA 和 MRN-CSG DNA 修复机制。洞察框本研究调查了乳腺肿瘤样本（n = 60），并确定了四种 miRNA（miR-1-3p、miR-210-3p、miR-16-5p 和 miR-34a-5p），它们与对 DNA 损伤修复至关重要的 MRN 检查点传感器基因（MRN-CSG）相互作用。通过筛选 7711 种天然化合物，发现两种化合物（F0870-0001 和 F0922-0471）的结合能最低（ΔG = -8.4 至 -11.6 kcal/mol），可靶向两种常见的 miRNA（miR-1-3p 和 miR-34a-5p）。另一种天然化合物（PubChem id-5 281 614，ΔG = -6.2 至 -7.3 kcal/mol）结合了所有 MRN-CSG 成分，而 F6782-0723 则针对 RAD50 和 NBN。这些化合物显示出很强的结合稳定性、良好的 MMGBSA 值和最小的解离常数。分子动力学模拟证实了这些化合物的稳定性和类药物特性，表明它们具有通过调节 miRNA 和 MRN-CSG DNA 修复机制来治疗乳腺癌的潜力。

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Multi-target therapeutic modulation with natural compounds towards DNA repair MRN-checkpoint sensor genes (MRN-CSGs) and oncogenic miRNAs in breast cancer patients: a Clinico-Informatic study.

Breast cancer, more prevalent in women, often arises due to abnormalities in the MRN-checkpoint sensor genes (MRN-CSG), responsible for DNA damage detection and repair. Abnormality in this complex is due to the suppression of various effectors such as siRNAs, miRNAs, and transcriptional factors responsible for breast tumor progression. This study analyzed breast tumor samples (n = 60) and identified four common miRNAs (miR-1-3p, miR-210-3p, miR-16-5p, miR-34a-5p) out of 12, exploring their interactions with MRN-CSG. The 3D structures of these miRNA-MRN-CSG complexes displayed strong thermodynamic stability. Screening 7711 natural compounds resulted in two natural compounds (F0870-0001 and F0922-0471) with the lowest ligand binding energies (ΔG = -8.4 to-11.6 kcal/mol), targeting two common miRNAs. Docking results showed that one natural compound (PubChem id-5 281 614) bound to all MRN-CSG components (ΔG = -6.2 to -7.3 kcal/mol), while F6782-0723 bound only to RAD50 and NBN. These compounds exhibited minimal dissociation constants (Kd and Ki) and thermodynamically stable minimum free energy (MMGBSA) values. Molecular dynamics simulations indicated highly stable natural compound-MRN-CSG complexes, with consistent RMSD, RMSF, and strong residual correlation. These top-selected compounds displayed robust intermolecular H-bonding, low carcinogenicity, low toxicity, and drug-like properties. Consequently, these compounds hold promise for regulating miRNA and MRN-CSG DNA repair mechanisms in breast cancer therapy. Insight Box: This study investigated breast tumor samples (n = 60) and identified four miRNAs (miR-1-3p, miR-210-3p, miR-16-5p, miR-34a-5p) that interact with MRN-checkpoint sensor genes (MRN-CSG), crucial for DNA damage repair. Screening 7711 natural compounds highlighted two compounds (F0870-0001 and F0922-0471) with the lowest binding energies (ΔG = -8.4 to -11.6 kcal/mol), targeting two common miRNAs (miR-1-3p and miR-34a-5p). Another natural compound (PubChem id-5 281 614, ΔG = -6.2 to -7.3 kcal/mol) bound all MRN-CSG components, while F6782-0723 targeted RAD50 and NBN. These compounds showed strong binding stability, favorable MMGBSA values, and minimal dissociation constants. Molecular dynamics simulations confirmed the stability and drug-like properties of these compounds, indicating their potential in breast cancer therapy by modulating miRNA and MRN-CSG DNA repair mechanisms.

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来源期刊

Integrative Biology 生物-细胞生物学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

1 months

期刊介绍： Integrative Biology publishes original biological research based on innovative experimental and theoretical methodologies that answer biological questions. The journal is multi- and inter-disciplinary, calling upon expertise and technologies from the physical sciences, engineering, computation, imaging, and mathematics to address critical questions in biological systems. Research using experimental or computational quantitative technologies to characterise biological systems at the molecular, cellular, tissue and population levels is welcomed. Of particular interest are submissions contributing to quantitative understanding of how component properties at one level in the dimensional scale (nano to micro) determine system behaviour at a higher level of complexity. Studies of synthetic systems, whether used to elucidate fundamental principles of biological function or as the basis for novel applications are also of interest.