Discovery of small molecular inhibitors for interleukin-33/ST2 protein-protein interaction: a virtual screening, molecular dynamics simulations and binding free energy calculations.
Tan Thanh MaiPhuc Gia NguyenMinh-Tri LeThanh-Dao TranPhuong Nguyen Hoai HuynhDieu-Thuong Thi TrinhQuoc-Thai NguyenKhac-Minh ThaiPublished in: Molecular diversity (2022)
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.
Keyphrases
- molecular dynamics simulations
- molecular docking
- clinical trial
- protein protein
- binding protein
- molecular dynamics
- crystal structure
- drug discovery
- emergency department
- high throughput
- randomized controlled trial
- quality improvement
- electronic health record
- dna binding
- artificial intelligence
- big data
- deep learning
- risk assessment
- phase ii