a School of Pharmaceutical Sciences , Jilin University , Changchun , People's Republic of China.
b Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry , Jilin University , Changchun , People's Republic of China.
J Biomol Struct Dyn. 2018 Nov;36(14):3705-3717. doi: 10.1080/07391102.2017.1396256. Epub 2017 Nov 6.
Transforming growth factor type 1 receptor (ALK5) is kinase associated with a wide variety of pathological processes, and inhibition of ALK5 is a good strategy to treat many kinds of cancer and fibrotic diseases. Recently, a series of compounds have been synthesized as ALK5 inhibitors. However, the study of their selectivity against other potential targets remains elusive. In this research, a data-set of ALK5 inhibitors were collected and studied based on the combination of 2D-QSAR, molecular docking and molecular dynamics simulation. The quality of QSAR models were assessed statistically by F, R, and R, proved to be credible. The cross-validations for the models (q = 0.571 and 0.629, respectively) showed their robustness, while the external validations (r = 0.703 and 0.764, respectively) showed their predictive power. Besides, the predicted binding free energy results calculated by MM/GBSA method were in accordance with the experimental data, and the van der Waals energy term was the factor that had the most significant impact on ligand binding. What is more, several important residues were found to significantly affect the binding affinity. Finally, based on our analyses above, a proposed series of molecules were designed.
转化生长因子-β 型受体 1（ALK5）是一种与多种病理过程相关的激酶，抑制 ALK5 是治疗多种癌症和纤维化疾病的有效策略。最近，已经合成了一系列作为 ALK5 抑制剂的化合物。然而，它们对其他潜在靶点的选择性研究仍难以捉摸。在这项研究中，基于二维定量构效关系（2D-QSAR）、分子对接和分子动力学模拟的组合，收集和研究了一组 ALK5 抑制剂。通过 F、R 和 r 统计评估了 QSAR 模型的质量，证明了其可靠性。模型的交叉验证（q=0.571 和 0.629）表明了它们的稳健性，而外部验证（r=0.703 和 0.764）表明了它们的预测能力。此外，通过 MM/GBSA 方法计算的预测结合自由能结果与实验数据一致，范德华能项是对配体结合影响最大的因素。更重要的是，发现了几个重要的残基对结合亲和力有显著影响。最后，基于我们的分析，设计了一系列建议的分子。
