Molecular Dynamics Simulation of Pyruvate Dehydrogenase Kinase 4 with Saroglitazar

Abstract

Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is currently the most widespread chronic liver condition, yet no approved pharmacological treatment. Pyruvate Dehydrogenase Kinase 4 (PDK4) plays a crucial role in metabolism by inhibiting the pyruvate dehydrogenase complex, shifting cellular energy usage toward fatty acid oxidation. Saroglitazar, a dual PPAR-α/γ agonist, has shown promise in treating metabolic disorders, but its interaction with PDK4 remains unclear. In modern drug discovery, computational methods have become essential for speeding up research while minimising costs.

Methods: The Study investigated the binding potential of Saroglitazar with PDK4 through structure-based virtual screening. Molecular docking predicted that Saroglitazar (CID-60151560) fits well within PDK4 active site. Subsequently, 100 ns molecular dynamics (MD) simulations were conducted using GROMACS and the CHARMM36 force field. Stability parameters such as RMSD, RMSF, hydrogen bonding, radius of gyration and binding free energies were analyzed. Active site residues were identified using the CDD server and BIOVIA Discovery Studio, with simulations performed in DESMOND.

Result: Saroglitazar binds strongly and steadily to PDK4, showing binding energy of -91.05 kcal/mol and a high LibDock score of 141.465. Minimal structural deviations and favourable MM-PBSA calculations further supported its potential.

Conclusion: Saroglitazar’s capacity to modulate PDK4 activity provides a biological foundation for its metabolic disease treatment.