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Identification of Potential Inhibitors Against the TGF-β/BMPs-Activin Receptor- like Kinase 1 Signal Pathway

Author(s):

Miao-Miao Wu*, Mei-Lin Liu, Jing Zhou, Yi-Da Wang, Chuan-Fang Wu and Jin-Ku Bao   Pages 1 - 15 ( 15 )

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 key role in TGF-β signaling, discovering inhibitors of ALK1 to block TGF-β signaling for 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.

Affiliation:

Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan, Key Laboratory of Bio-Resource and Eco-Environment of Ministry of Education, College of Life Sciences, Sichuan University, Chengdu 610065, Sichuan



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