Molecular docking and structure-based pharmacophore modeling identify putative TRPC5-binding candidates as an exploratory step toward modulators for focal segmental glomerulosclerosis

Focal Segmental Glomerulosclerosis (FSGS) is a primary aetiology of nephrotic syndrome and progressive renal insufficiency, primarily associated with podocyte injury and substantial proteinuria. Modern treatment methods, such corticosteroids and different immunosuppressive medicines, sometimes only lead to limited remission and can have bad side effects. Transient Receptor Potential Canonical 5 (TRPC5) channels have surfaced as prospective therapeutic targets due to their role in calcium-mediated cytoskeletal remodelling in podocytes. This study employed a structure-based pharmacophore modelling and virtual screening workflow to identify putative TRPC5-binding candidates. The pharmacophore model was not statistically validated (for example, by receiver operating characteristic (ROC) analysis or enrichment factor calculation) and was therefore used only as an exploratory structure-based screening filter. The crystal structure of the TRPC5-Clemizole complex acted as the structural model for making pharmacophore models, which were then tested against the ZINC chemical database. Molecular docking, interaction analysis, and molecular dynamics simulations were used to check the binding stability and structural behaviour of promising candidates in the TRPC5 binding pocket. The workflow identified several candidate compounds that showed more favourable docking scores and, over the simulated trajectories, apparent conformational stability relative to the reference ligand Clemizole. These compounds engaged residues within the binding pocket and, within the limits of the simulation, maintained stable protein-ligand complexes. It should be emphasised that these are preliminary computational hits: no inhibitory activity, selectivity, or therapeutic effect was demonstrated. The predictions require formal pharmacophore validation, selectivity testing against related TRP channels, and experimental confirmation through binding and functional assays before any conclusions regarding TRPC5 modulation or therapeutic potential in FSGS can be drawn.