新型1,3,4-恶二唑衍生物对PARP-1抑制剂的抗癌活性:一种计算机方法

Q2 Pharmacology, Toxicology and Pharmaceutics
Gowramma Byran, P. Patel, Preeya Negi, Sowmiya Arun, Kaviarasan Lakshmanan, K. Rajagopal, G. Swaminathan
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引用次数: 0

摘要

核酶聚(adp -核糖)聚合酶-1 (PARP-1)控制细胞周期、DNA修复、转录和复制过程。本研究以奥拉帕尼和鲁卡帕尼作为标准药物进行结果比较。根据以往的研究资料,1,3,4-恶二唑片段具有多向生物活性,具有较高的抗癌活性。本研究旨在利用Schrodinger套件2022-1对含1,3,4-噻二唑衍生物的PARP1抑制剂进行基于硅配体的筛选,以鉴定命中点,并对铅分子进行MMGBSA和分子动力学模拟。以苯氧乙酸、1-萘氧基乙酸、2-萘氧基乙酸和胡椒酰酸为原料,设计了32个1,3,4-恶二唑衍生物。分子对接(XP)研究在4ZZZ之间进行。结合亲和值在-8.52 ~ -3.52 kcal/mol之间。观察了蛋白质与配体之间的二维相互作用。根据结合亲和力值和ADMET结果,选择前10个类似物进行MM-GBSA。以苯氧乙酸、1-萘氧基乙酸、2-萘氧基乙酸和胡椒酰酸为原料,设计了32个1,3,4-恶二唑衍生物。分子对接(XP)研究在4ZZZ之间进行。PDB和设计的类似物的结合亲和值在-8.52 ~ -3.52 kcal/mol之间。观察到蛋白质和配体之间的二维相互作用。根据结合亲和力值和ADMET结果,选择前10个类似物进行MM-GBSA。顶级化合物的dg - binding评分在-2.30 ~ -60.67 kcal/mol之间,选择类似物D4进行100ns的MD模拟研究。分子动力学(MD)研究结果表明,D4与氨基酸残基相互作用,配体与蛋白质相互作用稳定在58 ~ 90ns之间。计算机研究的结果表明,化学物质A1, A3, B1, B2, B3, B4, C1, C6, D1和D4可能对乳腺癌具有显著的活性,具有潜在的治疗益处,并且在进一步开发后可能有用。综上所述,从1,3,4-恶二唑衍生的许多分子对PARP-1具有高亲和力。计算机研究的结果表明,化学物质A1, A3, B1, B2, B3, B4, C1, C6, D1和D4可能对乳腺癌具有显著的活性,具有潜在的治疗益处,并且在进一步开发后可能有用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Anticancer Activity of Novel 1,3,4-oxadiazole Derivatives against PARP-1 Inhibitors: An In-silico Approach
Nuclear enzyme poly (ADP-ribose) polymerase-1 (PARP-1) controls the cell cycle, DNA repair, transcription, and replication processes. In this study, olaparib and rucaparib have been taken as standard drugs for comparison of results. As per previous research data, 1,3,4-Oxadiazole moiety has multidirectional biological activity and shows high activity against cancer. This study aimed to carry out the in silico ligand-based screening for the identification of hits for PARP1 inhibitors bearing 1,3,4-thiadiazole derivatives using Schrodinger suite 2022-1 and to perform MMGBSA and molecular dynamics simulation for lead molecules. A total of 32 derivatives of 1,3,4-Oxadiazole were designed with four different acids: phenoxy acetic acid, 1-Naphthoxy acetic acid, 2-Naphthoxy acetic acid, and piperonylic acid. Molecular docking (XP) studies were performed between 4ZZZ.pdb and the designed analogues, and the binding affinity values lay in the range of -8.52 to -3.52 kcal/mol. 2D interactions between the protein and the ligand were observed. Based on the binding affinity values and ADMET results, top 10 analogues were selected for performing MM-GBSA.A total of 32 derivatives of 1,3,4-Oxadiazole were designed with four different acids that are Phenoxy acetic acid, 1-Naphthoxy acetic acid, 2-Naphthoxy acetic acid, and Piperonylic acid. Molecular docking (XP) studies were performed between 4ZZZ.pdb and the designed analogues and the binding affinity values lie in the range of -8.52 to -3.52 kcal/mol. 2D interactions between the protein and the ligand are observed. Based on the binding affinity values and ADMET results top 10 analogues were selected for performing MM-GBSA. The dG-bind score of the top compounds varied from -2.30 to -60.67 kcal/mol, and analogue D4 was selected for MD simulation studies for 100ns. Results of Molecular dynamics (MD) studies showed that D4 interacted with amino acid residues, and the ligand-protein interaction stabilized from 58-90ns. The in silico study's findings suggested that the chemicals A1, A3, B1, B2, B3, B4, C1, C6, D1, and D4 might be significantly active against breast cancer with potential therapeutic benefits and are likely to be useful after further development. In conclusion, numerous molecules exhibit a high affinity for PARP-1 when derived from 1,3,4-oxadiazole. The in silico study's findings suggested that the chemicals A1, A3, B1, B2, B3, B4, C1, C6, D1, and D4 might be significantly active against breast cancer with potential therapeutic benefits and are likely to be useful after further development.
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来源期刊
Current Bioactive Compounds
Current Bioactive Compounds Pharmacology, Toxicology and Pharmaceutics-Pharmacology, Toxicology and Pharmaceutics (all)
CiteScore
1.90
自引率
0.00%
发文量
112
期刊介绍: The journal aims to provide comprehensive review articles on new bioactive compounds with proven activities in various biological screenings and pharmacological models with a special emphasis on stereoeselective synthesis. The aim is to provide a valuable information source of bioactive compounds synthesized or isolated, which can be used for further development of pharmaceuticals by industry and academia. The journal should prove to be essential reading for pharmacologists, natural product chemists and medicinal chemists who wish to be kept informed and up-to-date with the most important developments on new bioactive compounds of natural or synthetic origin, including their stereoeselective synthesis.
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