Computational identification of potential tissue plasminogen activator (tPA) inhibitors from Paris polyphylla phytoconstituents through molecular docking and molecular dynamics simulations for anti-inflammatory therapy

Abstract

Plant-derived bioactive compounds exploration presents a good approach to discovering new anti-inflammatory agents. Phytoconstituents of Paris polyphylla were explored as an inhibitor of tissue plasminogen activator (tPA) in the present study using an integrated in silico strategy. Molecular docking demonstrated that some of the compounds were highly docked to the tPA active site, with Disogluside docking the best (−10.1 kcal/mol) in comparison to the co-crystal ligand (−10.1 kcal/mol) and the reference drug Nimesulide (−7.2 kcal/mol). Interaction analysis revealed that Disogluside was able to establish stable hydrogen bonds with key catalytic residues such as Thr175, Ser195, Gly216 and Gly219, and established strong hydrophobic interactions. The stability of the Disogluside–tPA complex was confirmed by molecular dynamics simulations (200 ns) with stable RMSD and minimal structural fluctuations. In addition, MM-GBSA computations revealed a favorable binding free energy (ΔGbind = −65.04 ± 4.82 kcal/mol), which was primarily driven by van der Waals and lipophilic interactions. The results indicate that Disogluside can be a potential tPA inhibitor with anti-inflammatory implications and should be investigated by additional experiments.