Disrupting TNF-α and TNFR1 interaction: Computational insights into the potential of D-Pinitol as an anti-inflammatory therapeutic

Title : Disrupting TNF-α and TNFR1 interaction: Computational insights into the potential of D-Pinitol as an anti-inflammatory therapeutic

Abstract:

Tumor Necrosis Factor alpha (TNF-α) plays a critical role in the progression of inflammatory and autoimmune diseases by mediating pro-inflammatory pathways, making it a pivotal target for therapeutic intervention.^1,2 D-Pinitol, a natural product with established anti-inflammatory and antioxidant properties, has been identified as a promising small-molecule inhibitor of TNF-α.³ Beyond its anti-inflammatory effects, D-Pinitol also exhibits antidiabetic, antioxidant, and anticancer activities, highlighting its broad therapeutic potential.¹ This study employs an integrative computational approach, combining molecular docking, discrete molecular dynamics (DMD), and normal mode analysis (NMA), to investigate the inhibitory mechanism of D-Pinitol on the TNF-α/TNFR1 receptor complex.

Using a hybrid template-based and ab initio docking strategy, a model of the TNF-α/TNFR1 complex was generated. DMD calculations on the protein-protein complex identified three flexible regions with high binding potential for D-Pinitol, and docking studies and NMA simulations reveal that D-Pinitol preferentially binds within the central hydrophobic pocket of TNF-α. Specifically, D-Pinitol showed an enhanced binding energy for a distorted conformation of the protein complex and an increased number of stabilizing interactions for it, suggesting that D-Pinitol acts inducing significant structural distortions in TNF-α structure and disrupting its interaction with TNFR1.

This mechanism differs from traditional inhibitors, which often target the protein-protein interface. Comparative analysis with other natural product inhibitors, including EGCG and Japonicone A,⁴ highlights D-Pinitol's unique approach. By leveraging structural distortions and non-traditional inhibition pathways, D-Pinitol opens new avenues for targeting protein-protein interactions in cytokine-mediated disorders.

Biography:

Dr. Ferran Acuña-Parés studied Chemistry at the Girona University, Spain, and graduated as MS in 2012. He then joined the QBIS-CAT research group at the Institute of Computational Chemistry and Catalysis (IQCC) in the same university. He conducted his PhD studies under the supervision of Prof. Josep Maria Luis and Prof. Julio Lloret-Fillol, earning his degree in 2016. After one-year postdoc supervised by Prof. Julio Lloret-Fillol at the Catalonian Institute of Chemical Research (ICIQ), Spain, he obtained the position of an Associate Professor at the Universidad Internacional de la Rioja (UNIR). He has published 16 research articles in JCR journals.