INSILICO ANALYSIS OF TRIPHALA-DERIVED POLYPHENOLS AS INHIBITORS OF TIR-TIR HOMODIMERIZATION IN THE INFLAMMATORY PATHWAY

Durgadevi RajendranNalini E^*

• School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, India

The downstream signaling of Nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway is mediated by the adaptor protein myeloid differentiation primary response gene 88 (MyD88). TIR-domain present in MyD88 plays a pivotal role in regulating the expression of pro-inflammatory cytokines. While synthetic drugs including M20, TJ-M2010-5, etc, were studied to mitigate the over-expression of MyD88, their prolonged usage has been known to cause adverse side reactions, highlighting the need for potential risk-free drug. An Ayurvedic formulation named Triphala, which is rich in polyphenols and traditionally used to treat various ailments was selected for the investigation. Although polyphenols are gaining attention as anti-inflammatory agents, their precise mode of action remains insufficiently understood. Previous studies have explored the anti-inflammatory properties of Triphala in a broad spectrum, but this study notably concentrates on the interactions of Triphala-derived polyphenols against the TIR-domain of MyD88 adaptor protein in the NF-κB signaling pathway. This study employs computational docking and MD simulation to study the interaction and stability of polyphenols with the target protein. The polyphenols were virtually docked with TIR-domain of MyD88 using AutoDock tools 1.5.7. From which top 3 proteinpolyphenol complexes with the highest binding affinities were taken and subjected to MD simulation for 200 ns to evaluate their interaction properties in detail. MD simulation findings corroborated the docking results, in which two complexes (protein-punicalagin and proteinchebulagic acid) have shown better interaction patterns. MD trajectory displays that the polyphenol binding has enhanced the stability of target protein by exhibiting the lower RMSD (~0.25 nm), SASA (~96.848-100.666 nm²), and stabilized Rg (~1.50-1.53 nm) of punicalagin and chebulagic acid complexes when compared to the reference complex. Our findings have supported the hypothesis that Triphala polyphenols can interact with the TIR-domain of MyD88 thereby inhibiting the production of inflammatory cytokines. This study provides a combo of computational validation for specific molecular target and mechanistic insight of Triphala-derived polyphenols into the inhibition of inflammation.