Abstract
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.
Keywords: ALK1, molecular docking, virtual screening, molecular dynamics simulation, potential inhibitors, TGF-β.
Graphical Abstract
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