Structural insight and analysis of TLR4 interactions with IAXO-102, TAK-242 and SN-38: an in silico approach.

Introduction: Toll-like receptor 4 (TLR4) has attracted interest due to its role in chemotherapy-induced gastrointestinal inflammation. This structural study aimed to provide in silico rational of the recognition and potential binding of TLR4 ligands IAXO-102, TAK-242, and SN-38 (the toxic metabolite of the chemotherapeutic irinotecan hydrochloride), which could contribute to rationale development of therapeutic anti-inflammation drugs targeting TLR4 in the gastrointestinal tract.

Methods: In silico docking was performed between the human TLR4-MD-2 complex and ligands (IAXO-102, TAK-242, SN-38) using Autodock Vina, setting the docking grids to cover either the upper or the lower bound of TLR4. The conformation having the lowest binding energy value (kcal/mol) was processed for post-hoc analysis of the best-fit model. Hydrogen bonding was calculated by using ChimeraX.

Results: Binding energies of IAXO-102, TAK-242 and SN-38 at the upper bound of TLR4-MD-2 ranged between - 3.8 and - 3.1, - 6.9 and - 6.3, and - 9.0 and - 7.0, respectively. Binding energies of IAXO-102, TAK-242 and SN-38 at the lower bound ranged between - 3.9 and - 3.5, - 6.5 and - 5.8, and - 8.2 and - 6.8, respectively. Hydrogen bonding at the upper bound of TLR4/MD-2 with IAXO-102, TAK-242 and SN-38 was to aspartic acid 70, cysteine 133 and serine 120, respectively. Hydrogen bonding at the lower bound of TLR4-MD-2 with IAXO-102, TAK-242 and SN-38 was to serine 528, glycine 480 and glutamine 510, respectively.

Conclusion: The in silico rational presented here supports further investigation of the binding activity of IAXO-102 and TAK-242 for their potential application in the prevention of gastrointestinal inflammation caused by SN-38.