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Journal of molecular modeling
Mar 24, 2025;31 (4): 124.

Interactions of flavonoid and coumarin derivative compounds with transforming growth factor-beta receptor 1 (TGF-βR1): integrating virtual screening, molecular dynamics, maximum common substructure, and ADMET approaches in the treatment of idiopathic pulmonary fibrosis.

Erman Salih Istifli, Paulo A Netz
Author Information
  1. Erman Salih Istifli: Department of Biology, Adana, Faculty of Science and Literature, Cukurova University, Adana, Turkey. ermansalih@gmail.com. ORCID
  2. Paulo A Netz: Theoretical Chemistry Group, Institute of Chemistry, Universidade Federal Do Rio Grande Do Sul, Porto Alegre, RS, Brazil. netz@iq.ufrgs.br. ORCID
PMID: 40126695 DOI: 10.1007/s00894-025-06338-3

Abstract

CONTEXT: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease characterized by very limited treatment options and significant side effects from existing therapies, highlighting the urgent need for more effective drug-like molecules. Transforming growth factor-beta receptor 1 (TGF-βR1) is a key player in the pathogenesis of IPF and represents a critical target for therapeutic intervention. In this study, the potential of plant-derived flavonoid and coumarin compounds as novel TGF-βR1 inhibitors was explored. A total of 1206 flavonoid and coumarin derivatives were investigated through a series of computational approaches, including drug-like filtering, virtual screening, molecular docking, 200-ns molecular dynamics (MD) simulations in triplicate, maximum common substructure (MCS) analysis, and absorption-distribution-metabolism-excretion-toxicity (ADMET) profiling. 2',3',4'-trihydroxyflavone and dicoumarol emerged as promising plant-based hit candidates, exhibiting comparable docking scores, MD-based structural stability, and more negative MM/PBSA binding free energy relative to the co-crystallized inhibitor, while surpassing pirfenidone in these parameters and demonstrating superior pharmacological properties. In light of the findings from this study, 2',3',4'-trihydroxyflavone and dicoumarol could be considered novel TGF-βR1 inhibitors for IPF treatment, and it is recommended that their structural optimization be pursued through in vitro binding assays and in vivo animal studies.
METHODS: The initial dataset of 1206 flavonoid and coumarin derivatives was filtered for drug-likeness using Lipinski's Rule of Five in the ChemMaster-Pro 1.2 program, resulting in 161 potential candidates. These compounds were then subjected to virtual screening against the TGF-βR1 kinase domain (PDB ID: 6B8Y) using AutoDock Vina 1.2.5, identifying the top three hit compounds-dicoumarol, 2',3',4'-trihydroxyflavone, and 2',3'-dihydroxyflavone. These hits underwent further exhaustive molecular docking for refinement of docking poses, followed by 200-ns MD simulations in triplicate using the AMBER03 force field in GROMACS. Subsequently, the binding free energies were calculated using the Molecular Mechanics/Poisson-Boltzmann Surface Area (MM/PBSA) method. MCS analysis was conducted to determine shared structural features among the top three hits, while ADMET properties were predicted using Deep-PK, a deep learning-based platform. Finally, the ligand-protein interactions were further visualized, analyzed, and rendered using ChimeraX, Discovery Studio Visualizer, and Visual Molecular Dynamics (VMD) program.

Keywords

ADMET Idiopathic pulmonary fibrosis Maximum common substructure Molecular dynamics Plant-based compounds Virtual screening

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Grants

  1. 001/Conselho Nacional de Desenvolvimento Científico e Tecnológico
  2. 001/Conselho Nacional de Desenvolvimento Científico e Tecnológico
  3. 001/Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  4. 001/Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
  5. FBA202012708/Çukurova Üniversitesi

MeSH Term

Coumarins
Molecular Dynamics Simulation
Flavonoids
Molecular Docking Simulation
Humans
Receptor, Transforming Growth Factor-beta Type I
Idiopathic Pulmonary Fibrosis
Protein Binding
Binding Sites

Chemicals

Coumarins
Flavonoids
Receptor, Transforming Growth Factor-beta Type I
Journal Article

Word Cloud

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