Identifying Natural Sonic Hedgehog Signalling Pathway Modulators with Potential Antifibrotic Activity in Chronic Kidney Disease: An in silico approach

Abstract Chronic kidney disease (CKD), often following unresolved acute kidney injury (AKI), is characterised by persistent fibrosis induced by several pathways, such as Sonic Hedgehog (SHH). Reactivation of the SHH pathway facilitates the profibrotic communication between epithelial cells and fibroblasts, contributing to CKD progression. In this study, we explored the inhibitory potential of three natural bioactive compounds against SHH pathway receptors: SHH protein, GLi, and SMO. Molecular docking, followed by 100 ns molecular dynamics simulations, was performed to assess binding stability and conformational behaviour. Key parameters, including RMSD, RMSF, hydrogen bonding, principal component analysis (PCA), and free energy landscape, were evaluated to understand dynamic interactions. The binding free energy was also calculated based on the MM/GBSA method. The three selected ligands (Kaempferol, Quercetin, and Naringenin) showed the highest binding affinity compared to other ligands. All these ligands showed favourable energy profiles, with significant interactions influencing structural flexibility and energetics of the SHH pathway receptors. These findings suggest that the selected compounds may effectively target SHH-mediated profibrotic signalling, offering an effective strategy to mitigate CKD progression through natural compound-based inhibition.