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.