Repurposing of Thalidomide as a Potential Therapeutic Agent for Idiopathic Pulmonary Fibrosis: An In Silico Molecular Docking Study

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease with median survival of three to five years and only two approved therapies, pirfenidone and nintedanib, neither of which halts or reverses fibrosis. Drug repurposing offers a fast, low-cost route to new candidates by exploiting molecules with established safety profiles. Thalidomide possesses well-characterised immunomodulatory, anti-TNF-α, and anti-angiogenic properties, and is the only drug shown in a randomised trial to improve a patient-relevant outcome in IPF. This study evaluated thalidomide's anti-fibrotic potential using in silico molecular docking against nine protein targets spanning key fibrogenic pathways, including TGF-β/Smad signalling, TNF-α, integrin-mediated TGF-β activation, and PI3K/Akt/mTOR signalling, using AutoDock/AutoDock Vina. Protein and ligand structures were prepared, energy-minimised, and docked within defined grid boxes, with binding affinity, inhibition constants, and interactions analysed. Thalidomide engaged all nine targets favourably, with affinities spanning roughly 825-fold in potency. The strongest interaction occurred at TGFβR1 (−9.659 kcal/mol, Ki ≈ 83.16 nM), followed by 4TZ4, 5E8Y, and AKT1, all below −8.0 kcal/mol. A recurring pharmacophore, an acidic hydrogen-bond anchor with aromatic stacking, characterised the strongest complexes. These findings position thalidomide as a mechanistically plausible, computationally supported candidate for further validation as a repurposed anti-fibrotic agent in IPF.