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Exploring the Inhibitory Effects of Compounds for the Treatment of Liver Fibrosis: A Computational and Microscopic
Aneeqa Mehtab1, Hamid Ali1, Ijaz Ali1
1Department of Biosciences, COMSATS University Islamabad, Park Road, Tarlai Kalan, Islamabad, 44000, Pakistan.
Introduction:
Hepatic fibrosis, a chronic liver injury caused by autoimmune, alcoholic, viral, and non-alcoholic fatty liver disorders, leads to cirrhosis. Proteins that stimulate HSCs to initiate wound healing are suppressed as part of the treatment. This study aims to identify potential inhibitors of COX2, integrin, PDGF, TGF-β, and protein kinase C, validate in silico results, and compare inhibitory effects using scanning electron microscopy.
Methods:
A database was used to identify proteins of interest, and inhibitors against specific proteins previously reported were selected. Ligand-protein interactions were evaluated through docking simulations using MOE, and the resulting complexes were analyzed using SwissADME. The study involved five groups of male rats, each weighing 200-240 g. The first group was a control without treatment or fibrosis induction, the second group was a negative control with CCl4 injection, and groups 3, 4, and 5 received silymarin, rutin, and sorafenib treatments, respectively, in addition to CCl4.
Results:
The study demonstrated that three compounds-silymarin, rutin, and sorafenib-can inhibit six different proteins. Rutin interacts with multiple proteins and has a docking score of -7.5220. It acts as a P-gp substrate, crosses the blood-brain barrier persistently, and shows high gastrointestinal absorption.
Discussion:
This work demonstrates how computer-aided drug design can be used to identify potent molecules targeting COX2, PKC, integrin, Claudin 2, TGF-β, and PDGF, advancing drug management and therapy of liver fibrosis. In vivo studies indicate that silymarin is the most effective compound for reducing enzyme levels.
Conclusion:
Microscopic examination of the CCl4 group indicated hepatocellular necrosis, inflammation, fibrosis, and bile duct proliferation, characterized by enlarged ductal cells, bile ductules, and extensive hepatocyte necrosis. Treatment with rutin, silymarin, and sorafenib improved CCl4-induced liver damage. Among these, rutin treatment restored liver architecture, reduced inflammation, lessened fibrosis, and caused minimal hepatocellular damage. Silymarin treatment reduced fibrosis, tissue damage, and inflammatory cell infiltration. Sorafenib treatment caused minimal to moderate hepatocyte damage while improving liver function by decreasing inflammation and fibrosis.
Insights
This study identifies silymarin, rutin, and sorafenib as potential inhibitors for liver fibrosis by targeting key proteins. In vivo results show silymarin and rutin effectively reduce liver damage and fibrosis progression.
Area of Science:
- Pharmacology and Toxicology
- Computational Chemistry
- Hepatology
Background:
- Hepatic fibrosis, a precursor to cirrhosis, results from chronic liver injury due to various causes.
- Current treatments aim to suppress proteins that stimulate hepatic stellate cells (HSCs) to initiate wound healing.
Purpose of the Study:
- To identify potential inhibitors for key proteins involved in hepatic fibrosis, including COX2, integrin, PDGF, TGF-β, and protein kinase C (PKC).
- To validate in silico findings and compare the inhibitory effects of selected compounds in vivo.
Main Methods:
- Utilized a database to identify target proteins and selected known inhibitors.
- Performed molecular docking simulations (MOE) and analyzed ligand-protein interactions using SwissADME.
- Conducted in vivo studies using male rats with carbon tetrachloride (CCl4)-induced liver fibrosis, comparing silymarin, rutin, and sorafenib treatments against control groups.
Main Results:
- Identified silymarin, rutin, and sorafenib as inhibitors of six different target proteins.
- Rutin demonstrated significant interactions with multiple proteins, exhibiting a docking score of -7.5220, and favorable pharmacokinetic properties (P-gp substrate, blood-brain barrier penetration, high GI absorption).
- In vivo, all three compounds improved CCl4-induced liver damage, with rutin notably restoring liver architecture and reducing fibrosis.
Conclusions:
- Computer-aided drug design effectively identified potent molecules targeting key proteins in liver fibrosis.
- Silymarin emerged as the most effective compound in reducing enzyme levels in vivo.
- Rutin, silymarin, and sorafenib demonstrate therapeutic potential by mitigating liver fibrosis and associated damage.
