Integrated expression profiling and structure-based drug discovery identify EGFR as a druggable target and Tripterygium wilfordii phytochemicals as potential therapeutics for autosomal dominant polycystic kidney disease.
Abstract
Autosomal dominant polycystic kidney disease (ADPKD) is a progressive genetic disorder characterized by renal cyst formation and eventual kidney failure, with limited effective therapeutic options. In this study, we employed an integrated computational framework combining microarray-based gene expression profiling, network pharmacology, and structure-based drug discovery to identify potential therapeutic targets and phytochemical inhibitors. Differential expression analysis of the GSE7869 dataset (18 ADPKD vs. 3 controls) identified 233 significant genes, including 42 upregulated and 191 downregulated genes, with key dysregulated markers such as SFRP2 (log₂FC = 5.97) and G6PC (log₂FC = -5.94). Protein-protein interaction network analysis (178 nodes, 204 edges; p < 1.0 × 10⁻¹⁶) revealed central hub genes, including the ligand EGF. A library of 27 Tripterygium wilfordii phytochemicals was screened against the EGFR kinase domain (PDB ID: 1M17) using structure-based virtual screening. Top candidates, Luteolin and Triptonolide, exhibited superior binding affinities (-9.8 and -8.6 kcal/mol, respectively) compared to the reference drug Tolvaptan (-7.0 kcal/mol), supported by multiple hydrogen bonding and hydrophobic interactions within the active site. Molecular dynamics simulations over 500 ns supported the structural stability of the ligand-protein complexes. MM-PBSA analysis supported favorable binding, and interaction profiling showed stable hydrogen-bonding and hydrophobic contacts. Overall, the integrated analysis identifies EGFR as a potential therapeutic target in ADPKD and highlights Luteolin and Triptonolide as computationally prioritized phytochemical lead candidates for further investigation. However, all these findings have been established on the basis of computational studies alone and need further in vitro and in vivo validation.