Introduction: In many diseased states, especially fibrosis and cancer, TGF-β family members are overexpressed and the outcome of signaling is diverted toward disease progression. As the result of activin receptor-like kinase 1 (ALK1) plays a key role in TGF-β signaling, discovering inhibitors of ALK1 to block TGF-β signaling for a therapeutic benefit has become an effective strategy.

Methods: In this work, ZINC15894217 and ZINC12404282 were identified as potential ALK1 inhibitors using molecular docking, molecular dynamics simulation and MM/PBSA calculations studies. The analysis of energy decomposition found that Val208, Val216, Lys229, Gly283, Arg334 and Leu337 acted as crucial residues for ligand binding and system stabilizing.

Results: In addition, these compounds displayed excellent pharmacological and structural properties, which can be further evaluated through in vitro and in vivo experiments for the inhibition of ALK1 to be developed as drugs against fibrosis and tumor.

Conclusion: Overall, our study illustrated a time- and cost-effective computer aided drug design procedure to identify potential ALK1 inhibitors. It would provide useful information for further development of ALK1 inhibitors to improve disease related to TGF-β signal pathway.

简介：在许多疾病状态下，尤其是纤维化和癌症，TGF-β 家族成员过度表达，信号转导的结果会转向疾病进展。由于激活素受体样激酶 1 (ALK1) 在 TGF-β 信号传导中起关键作用，因此发现 ALK1 抑制剂来阻断 TGF-β 信号传导以获得治疗益处已成为一种有效策略。

方法：在这项工作中，通过分子对接、分子动力学模拟和 MM/PBSA 计算研究，将 ZINC15894217 和 ZINC12404282 确定为潜在的 ALK1 抑制剂。能量分解分析发现，Val208、Val216、Lys229、Gly283、Arg334 和 Leu337 是配体结合和系统稳定的关键残基。

结果：此外，这些化合物表现出优异的药理和结构特性，可以通过体外和体内实验进一步评估抑制 ALK1 的作用，从而开发出抗纤维化和肿瘤的药物。

结论：总体而言，我们的研究说明了一种具有时间和成本效益的计算机辅助药物设计程序来识别潜在的 ALK1 抑制剂。这将为进一步开发ALK1抑制剂以改善与TGF-β信号通路相关的疾病提供有用的信息。