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Discovery of small molecular inhibitors for interleukin-33/ST2 protein-protein interaction: a virtual screening, molecular dynamics simulations and binding free energy calculations.

ABSTRACT: The interleukin-1 receptor like ST2 has emerged as a potential drug discovery target since it was identified as the receptor of the novel cytokine IL-33, which is involved in many inflammatory and autoimmune diseases. For the treatment of such IL-33-related disorders, efforts have been made to discover molecules that can inhibit the protein-protein interactions (PPIs) between IL-33 and ST2, but to date no drug has been approved. Although several anti-ST2 antibodies have entered clinical trials, the exploration of small molecular inhibitors is highly sought-after because of its advantages in terms of oral bioavailability and manufacturing cost. The aim of this study was to discover ST2 receptor inhibitors based on its PPIs with IL-33 in crystal structure (PDB ID: 4KC3) using virtual screening tools with pharmacophore modeling and molecular docking. From an enormous chemical space ZINC, a potential series of compounds has been discovered with stronger binding affinities than the control compound from a previous study. Among them, four compounds strongly interacted with the key residues of the receptor and had a binding free energy < - 20 kcal/mol. By intensive calculations using data from molecular dynamics simulations, ZINC59514725 was identified as the most potential candidate for ST2 receptor inhibitor in this study.

SUBMITTER: Mai TT

PROVIDER: S-EPMC8760117 | biostudies-literature | 2022 Oct

REPOSITORIES: biostudies-literature

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Discovery of small molecular inhibitors for interleukin-33/ST2 protein-protein interaction: a virtual screening, molecular dynamics simulations and binding free energy calculations.

Mai Tan Thanh TT Nguyen Phuc Gia PG Le Minh-Tri MT Tran Thanh-Dao TD Huynh Phuong Nguyen Hoai PNH Trinh Dieu-Thuong Thi DT Nguyen Quoc-Thai QT Thai Khac-Minh KM

Molecular diversity 20220115 5

The interleukin-1 receptor like ST2 has emerged as a potential drug discovery target since it was identified as the receptor of the novel cytokine IL-33, which is involved in many inflammatory and autoimmune diseases. For the treatment of such IL-33-related disorders, efforts have been made to discover molecules that can inhibit the protein-protein interactions (PPIs) between IL-33 and ST2, but to date no drug has been approved. Although several anti-ST2 antibodies have entered clinical trials, ...[more]

PMID: 35031934

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Dataset Information

Discovery of small molecular inhibitors for interleukin-33/ST2 protein-protein interaction: a virtual screening, molecular dynamics simulations and binding free energy calculations.

Publications

Discovery of small molecular inhibitors for interleukin-33/ST2 protein-protein interaction: a virtual screening, molecular dynamics simulations and binding free energy calculations.

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