Predicting molecular mechanism of silymarin-potentiated diclofenac toxicity: Insight from molecular docking.

Silymarin was shown to enhance diclofenac toxicity by inducing the loss of mitochondrial membrane permeability (MMP) in Caco-2 cells, independent of endoplasmic reticulum stress. This study employed molecular docking to further investigate the potential interaction between silymarin and specific mitochondrial proteins involved in the loss of mitochondria integrity, aiming to elucidate the underlying mechanism of potentiation. The target proteins for our docking analysis included mitochondrial complex I and III, voltage-dependent anion-selective channel (VDAC), and cyclophilin D (CypD). Our results indicated that diclofenac could bind to both mitochondrial complex I and III. In contrast, silymarin exhibited a strong interaction with mitochondrial complex I with the binding energy (ΔG) -7.74 kcal/mol and the inhibition constant (Ki) 2.12 µM, while not showing significant interaction with mitochondrial complex III. Additionally, silymarin had the potential to induce the opening of mitochondrial permeability transition pore by binding with VDAC in the outer mitochondrial membrane with ΔG -6.08 kcal/mol and Ki 34.94 µM. However, silymarin did not exhibit significant interaction with CypD in the inner mitochondrial membrane. Therefore, mitochondrial complex I and VDAC could be the potentiation targets of silymarin, resulting in the disruption of mitochondria integrity and enhancing the toxicity of diclofenac.