The
zymogen protease Plasminogen (Plg) and its active form
plasmin (Plm) carry out important functions in the
blood clot disintegration (breakdown of
fibrin fibers) process. Inhibition of
plasmin effectively reduces fibrinolysis to circumvent heavy
bleeding. Currently, available Plm inhibitor
tranexamic acid (TXA) used for treating severe
hemorrhages is associated with an increased incidence of
seizures which in turn were traced to
gamma-aminobutyric acid antagonistic activity (GABAa) in addition to having multiple side effects. Fibrinolysis can be suppressed by targeting the three important protein domains: the kringle-2 domain of
tissue plasminogen activator, the kringle-1 domain of
plasminogen, and the
serine protease domain of
plasminogen. In the present study, one million molecules were screened from the
ZINC database. These
ligands were docked to their respective
protein targets using Autodock Vina, Schrödinger Glide, and ParDOCK/BAPPL+. Thereafter, the
drug-likeness properties of the
ligands were evaluated using Discovery Studio 3.5. Subsequently, we subjected the
protein-
ligand complexes to molecular dynamics simulation of 200 ns in GROMACS. The identified
ligands P76(ZINC09970930), C97(ZINC14888376), and U97(ZINC11839443) for each
protein target are found to impart higher stability and greater compactness to the
protein-
ligand complexes. Principal component analysis (PCA) implicates, that the identified
ligands occupy smaller phase space, form stable clusters, and provide greater rigidity to the
protein-
ligand complexes. Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) analysis reveals that P76, C97, and U97 exhibit better binding free energy (ΔG) when compared to that of the standard
ligands. Thus, our findings can be useful for the development of promising anti-
fibrinolytic agents.Communicated by Ramaswamy H. Sarma.