Multi-complex pharmacophore mapping for the repurposing of FDA drugs as HTLV-1 protease inhibitors: Toward novel anti-HTLV-1 therapeutics.

Human T-cell Leukemia Virus Type 1 (HTLV-1) protease (PR) is a critical enzyme involved in viral maturation and represents a key target for the development of antiviral therapeutics. Despite significant efforts to design novel inhibitors, many candidates have failed due to poor pharmacokinetic and safety profiles. In the present context, drug repurposing of FDA-approved compounds offers a rapid and cost-efficient strategy for identifying potential therapeutics. Thus, in this study, a multi-complex pharmacophore mapping approach was employed to explore the structural proteome of the HTLV-1 PR systematically. Multiple crystal structures of the protease in complex with inhibitors were analyzed to generate energy-based pharmacophore hypotheses that capture the essential features required for effective inhibition. A representative pharmacophore model was selected and used as a primary screening tool to identify FDA-approved drugs with complementary chemical features. The screened compounds were further subjected to molecular docking and binding energy evaluation to refine potential hits. Subsequently, triplicate molecular dynamics (MD) simulations incorporating enhanced sampling techniques, along with PCA-based FEL and DSSP analyses, reinforced the structure's stability and assessed the dynamic behavior of the protein-ligand complexes. Detailed analysis of binding interactions enabled the identification of structurally and energetically favorable candidates. Among them, the FDA-approved drug DB_FDA_1647 (Eliglustat) emerged as the most promising candidate, exhibiting favorable binding affinity, stable intermolecular interactions, and consistent structural stability throughout the molecular dynamics simulations. These findings highlight the potential of multi-complex pharmacophore mapping combined with drug repurposing as an effective strategy for developing novel anti-HTLV-1 therapeutics.