Structure-based discovery of interleukin-33 inhibitors: a pharmacophore modelling, molecular docking, and molecular dynamics simulation approach

ABSTRACT

Interleukin (IL)-33 is a new cytokine of the IL-1 family that is related to several inflammatory and autoimmune diseases. IL-33 binds to its ST2 receptor and leads to biological responses thereof. Currently, no drugs have been approved for the treatment of IL-33 related diseases. The aim of this study was to search for small molecules that inhibit the protein–protein interaction between IL-33 and ST2. A virtual screening was first performed to identify potential molecules that can bind IL-33. By analysing the interactions between key residues in the complex of IL-33/ST2, two pharmacophore hypotheses were then generated based on the ‘mimicry’ and ‘pair-rule’ principles. From a database of 62,074 compounds, 60 molecules satisfying the pharmacophore models were identified and docked to IL-33. Among 35 compounds successfully docked into the protein, 9 potential ligands in complex with IL-33 were selected for further analysis by molecular dynamics simulations. Based on the stability of the complexes and the interactions of each ligand with the key residues of IL-33, two compounds DB00158 and DB00642 were identified as the most potential inhibitors that can be further investigated as promising novel IL-33 inhibitory drugs.

KEYWORDS:

• Interleukin-33
• ST2 receptor
• protein-protein interaction inhibitors
• pharmacophore
• molecular docking
• molecular dynamics simulation

Acknowledgements

This research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 108.05-2018.15 for Quoc-Thai Nguyen; Vietnam National University Ho Chi Minh City under Grant number C2018-44-01 for Minh-Tri Le; and Domestic Master/PhD Scholarship Programme of Vingroup Innovation Foundation under Grant number VINIF.2019.TS.59 for Tan Thanh Mai.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

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Additional information

Funding

This work was supported by the Vietnam National Foundation for Science and Technology Development (NAFOSTED) [108.05-2018.15]; Vietnam National University Ho Chi Minh City [C2018-44-01]; Domestic Master/ PhD Scholarship Programme of Vingroup Innovation Foundation [VINIF.2019.TS.59].