Drug repurposing for psoriasis: virtual screening, molecular dynamics, and ADMET profiling for the identification of...

Psoriasis is a chronic dermatological disorder affecting approximately 43 million people globally, with current treatments limited by toxicity and high costs. Dihydrofolate reductase (DHFR), a crucial enzyme in folate metabolism essential for DNA synthesis, represents a validated therapeutic target for psoriasis. This study aimed to identify FDA-approved drugs with potential DHFR inhibitory activity using an integrated computational approach combining molecular docking, ADMET prediction, and molecular dynamics simulations. A total of 2311 FDA-approved drugs from DrugBank were docked against human DHFR (PDB ID: 1S3V). Ten compounds exhibited strong binding affinities (MolDock scores: -209.9 to -261.3 kcal/mol), with Velpatasvir showing the highest score (-261.3 kcal/mol), followed by Ledipasvir (-242.4 kcal/mol). ADMET profiling classified both compounds as Medium Priority. To evaluate binding stability, 20 ns triplicate MD simulations and MM-GBSA calculations were performed. Both compounds formed stable complexes, with mean protein RMSD values of 2.36 ± 0.10 Å (Velpatasvir) and 2.37 ± 0.26 Å (Ledipasvir). Velpatasvir demonstrated more consistent binding across replicates (RMSF: 2.79 ± 1.65 Å; MM-GBSA SD: 5.52 kcal/mol) compared to Ledipasvir (RMSF: 6.22 ± 2.12 Å; MM-GBSA SD: 13.01 kcal/mol). PCA and DCCM analyses revealed that Velpatasvir induced highly consistent motion patterns, while Ledipasvir exhibited more variable conformational sampling. Both compounds showed favourable binding free energies (Velpatasvir: -43.39 ± 5.52 kcal/mol; Ledipasvir: -49.19 ± 13.01 kcal/mol). These findings suggest Velpatasvir and Ledipasvir as promising DHFR inhibitors warranting experimental validation, and demonstrate drug repurposing as a cost-effective strategy for discovering novel psoriasis therapies.

The online version contains supplementary material available at https://doi.org/10.1007/s40203-026-00761-x.