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An In-Silico Identification of Potential Flavonoids against Kidney Fibrosis Targeting TGFβR-1
M D Hasanur Rahman1,2, Partha Biswas1,3, Dipta Dey1,4
1ABEx Bio-Research Center, East Azampur, Dhaka 1230, Bangladesh.
Abstract:
Fibrosis is a hallmark of progressive kidney diseases. The overexpression of profibrotic cytokine, namely transforming growth factor β (TGF-β) due to excessive inflammation and tissue damage, induces kidney fibrosis. The inhibition of TGF-β signaling is markedly limited in experimental disease models. Targeting TGF-β signaling, therefore, offers a prospective strategy for the management of kidney fibrosis. Presently, the marketed drugs have numerous side effects, but plant-derived compounds are relatively safer and more cost-effective. In this study, TGFβR-1 was targeted to identify the lead compounds among flavonoids using various computational approaches, such as ADME/T (absorption, distribution, metabolism, and excretion/toxicity) analysis, molecular docking, and molecular dynamics simulation. ADME/T screening identified a total of 31 flavonoids with drug-like properties of 31 compounds, a total of 5 compounds showed a higher binding affinity to TGFβR-1, with Epicatechin, Fisetin, and Luteolin ranking at the top three (-13.58, -13.17, and -10.50 kcal/mol, respectively), which are comparable to the control drug linagliptin (-9.074 kcal/mol). The compounds also exhibited outstanding protein-ligand interactions. The molecular dynamic simulations revealed a stable interaction of these compounds with the binding site of TGFβR-1. These findings indicate that flavonoids, particularly Epicatechin, Fisetin, and Luteolin, may compete with the ligand-binding site of TGFβR-1, suggesting that these compounds can be further evaluated for the development of potential therapeutics against kidney fibrosis. Further, in-vitro and in-vivo studies are recommended to support the current findings.
Insights
Flavonoids like Epicatechin, Fisetin, and Luteolin show promise for treating kidney fibrosis by inhibiting TGF-β signaling. Computational studies identified these compounds as potential therapeutics targeting TGFβR-1.
Area of Science:
- Biochemistry
- Pharmacology
- Computational Chemistry
Background:
- Kidney fibrosis, a key feature of progressive kidney diseases, is driven by transforming growth factor β (TGF-β) overexpression.
- Current therapeutic strategies targeting TGF-β signaling have limitations, necessitating novel approaches.
Purpose of the Study:
- To identify potential therapeutic compounds for kidney fibrosis by targeting TGFβR-1 using computational methods.
- To evaluate flavonoids as safer and cost-effective alternatives to existing drugs.
Main Methods:
- Absorption, Distribution, Metabolism, Excretion/Toxicity (ADME/T) analysis was performed on flavonoids.
- Molecular docking and molecular dynamics simulations were used to assess binding affinity and interactions with TGFβR-1.
- Lead compounds were identified based on drug-like properties and binding efficacy.
Main Results:
- 31 flavonoids exhibited favorable drug-like properties.
- Epicatechin, Fisetin, and Luteolin demonstrated high binding affinity to TGFβR-1, surpassing the control drug linagliptin.
- Molecular dynamics simulations confirmed stable interactions between these flavonoids and the TGFβR-1 binding site.
Conclusions:
- Flavonoids, particularly Epicatechin, Fisetin, and Luteolin, are promising candidates for kidney fibrosis therapeutics.
- These compounds may act by competitively inhibiting the ligand-binding site of TGFβR-1.
- Further in vitro and in vivo studies are warranted to validate these computational findings.
