Banerjee, S and Mahesh, Y and Prabhu, D and Sekar, K and Sen, P (2023) Identification of potent anti-fibrinolytic compounds against plasminogen and tissue-type plasminogen activator employing in silico approaches. In: Journal of Biomolecular Structure and Dynamics .
Full text not available from this repository.Abstract
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 (�G) 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. © 2023 Informa UK Limited, trading as Taylor & Francis Group.
| Item Type: | Journal Article |
|---|---|
| Publication: | Journal of Biomolecular Structure and Dynamics |
| Publisher: | Taylor and Francis Ltd. |
| Additional Information: | The copyright for this article belongs to Taylor and Francis Ltd. |
| Keywords: | molecular docking; molecular dynamics simulation; Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA); plasmin; principal component analysis (PCA); structure-based virtual screening |
| Department/Centre: | Division of Interdisciplinary Sciences > Computational and Data Sciences |
| Date Deposited: | 03 Jul 2023 07:12 |
| Last Modified: | 03 Jul 2023 07:12 |
| URI: | https://eprints.iisc.ac.in/id/eprint/82138 |
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