Computational design of PARP-1 inhibitors: QSAR, molecular docking, virtual screening, ADMET, and molecular dynamics simulations for targeted drug development.

IF 2.3 3区 环境科学与生态学 Q3 CHEMISTRY, MULTIDISCIPLINARY
N Najafi, M H Fatemi
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引用次数: 0

Abstract

Poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors have shown promise in treating various cancers with homologous recombination repair deficiencies, particularly in breast and ovarian cancers harbouring BRCA1/2 mutations. This study aimed to identify and optimize novel PARP-1 inhibitors using the phthalazinone scaffold, known for forming strong and selective interactions with the active site of PARP-1. Through a combination of Quantitative Structure-Activity Relationship (QSAR) modelling, molecular docking simulations, and virtual screening, we discovered compounds with significant anticancer potential. Both the Multiple Linear Regression (MLR) and Support Vector Machines (SVM) models, utilizing four selected molecular descriptors, demonstrated high predictive efficiency for inhibitory activity (MLR: r2  = 0.944, Q2cv (cross-validated correlation coefficient) = 0.921, root mean square error (RMSE) = 0.249; SVM: r2  = 0.947, Q2cv = 0.887, RMSE = 0.245). Molecular docking studies revealed that several new compounds exhibited strong interactions with key amino acids GLY 227A, MET 229A, PHE 230A, and TYR 246A within the PARP-1 active site, similar to those observed in reference inhibitors Olaparib and AZD2461. Then, the top-ranked compound's (3a) ligand-protein complex underwent a 200 ns molecular dynamics (MD) simulation, confirming stable binding and revealing a robust set of intermolecular interactions maintained under physiological conditions.

PARP-1抑制剂的计算设计:QSAR、分子对接、虚拟筛选、ADMET和靶向药物开发的分子动力学模拟。
聚(adp -核糖)聚合酶-1 (PARP-1)抑制剂在治疗各种同源重组修复缺陷的癌症中显示出前景,特别是在乳腺癌和卵巢癌中携带BRCA1/2突变。本研究旨在利用酞嗪酮支架鉴定和优化新型PARP-1抑制剂,酞嗪酮支架以与PARP-1活性位点形成强而选择性的相互作用而闻名。通过定量构效关系(QSAR)建模、分子对接模拟和虚拟筛选相结合,我们发现了具有显著抗癌潜力的化合物。多元线性回归(MLR)和支持向量机(SVM)模型均显示出较高的抑制活性预测效率(MLR: r2 = 0.944, Q2cv(交叉验证相关系数)= 0.921,均方根误差(RMSE) = 0.249;SVM: r2 = 0.947, Q2cv = 0.887, RMSE = 0.245)。分子对接研究显示,一些新化合物在PARP-1活性位点与关键氨基酸GLY 227A、MET 229A、PHE 230A和TYR 246A表现出强相互作用,类似于参考抑制剂Olaparib和AZD2461。然后,对排名第一的化合物(3a)配体-蛋白复合物进行200 ns分子动力学(MD)模拟,证实了稳定的结合,并揭示了生理条件下维持的一组强大的分子间相互作用。
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来源期刊
CiteScore
5.20
自引率
20.00%
发文量
78
审稿时长
>24 weeks
期刊介绍: SAR and QSAR in Environmental Research is an international journal welcoming papers on the fundamental and practical aspects of the structure-activity and structure-property relationships in the fields of environmental science, agrochemistry, toxicology, pharmacology and applied chemistry. A unique aspect of the journal is the focus on emerging techniques for the building of SAR and QSAR models in these widely varying fields. The scope of the journal includes, but is not limited to, the topics of topological and physicochemical descriptors, mathematical, statistical and graphical methods for data analysis, computer methods and programs, original applications and comparative studies. In addition to primary scientific papers, the journal contains reviews of books and software and news of conferences. Special issues on topics of current and widespread interest to the SAR and QSAR community will be published from time to time.
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