Silymarin as a potent polyphenol against metabolic disease pathways: A computational insight and ADMET/MM-PBSA analysis

Metabolic diseases, such as obesity, type 2 diabetes, etc., are becoming increasingly prevalent and pose major health challenges worldwide. Dysregulation of key metabolic regulators, including Carnitine Palmitoyltransferase 1 (CPT1) and Fatty Acid Binding Proteins (FABPs), plays a crucial role in the development of these diseases. In this study, computational approaches, including molecular docking, molecular dynamics simulations, and ADMET/MM-PBSA analysis, were employed to investigate the binding interactions and therapeutic potential of Silymarin against key metabolic disease-related targets, including CPT1, Peroxisomal Bifunctional Enzyme (PBFE), and Oxysterol receptor LXR-alpha (LXR). The highest binding affinity was observed with FABP1 and FABP4, while significant interactions were also found with LXR and PBFE. Molecular dynamics simulations demonstrated that the FABP1-Silymarin and FABP4-Silymarin complexes remained stable over time. The FABP4-Silymarin complex exhibited a compact structure, suggesting a potential inhibitory effect of Silymarin. Changes in RMSD and RMSF fluctuations indicated the effects of Silymarin on structural conformation. PCA showed that the presence of the Silymarin molecule exacerbated the movements of the structures. Moreover, the results showed that hydrophobic and hydrogen interactions between the ligand structure can lead to changes in the structure. MMPBSA calculations further confirmed favorable binding free energies for all studied targets, indicating strong ligand-protein interactions. Overall, Silymarin showed high binding affinity within the active sites of potential drug target proteins. The observed changes in protein-ligand complex stability, particularly for FABP1 and FABP4, highlight their antimicrobial and anti-inflammatory properties. These findings support the potential clinical application of Silymarin and its use in drug design for the treatment of metabolic diseases.