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

Abstract

Graphical 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. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-021-10359-4.

Exon variants associated with asthma and allergy1

“…There are also refined or repurposed treatment options as for example lenalidomide is targeting IKZF3 (44) or disulfiram which was used earlier to treat atopic dermatitis (45) and may be able to block gasdermins (46). There are also new treatment possibilities of small-molecule antagonists like MMG-11 on TLR1 (47) or ZINC59514725 on IL1RL1 (48).…”

Computational Cosolvent Mapping Analysis Leads to Identify Salicylic Acid Analogs as Weak Inhibitors of ST2 and IL33 Binding

“…74 However, VS methods use a static protein structure for hit identification and subsequent MD simulations are frequently needed to validate and refine the un-optimized protein−ligand interaction such as the protocol used by Mai et al's study. 72 The cosolvent-based simulations 37,38,[40][41][42]45 have the advantage of accounting for the dynamic interaction between the protein and the ligand and allowing for reshaping the binding site induced by the ligands. Although the cosolvent-based simulations are computationally more expensive than the VS methods for screening the same number of compounds, both approaches can be effective in different applications.…”

“…The in silico virtual screening (VS) method can be another powerful way to identify hit compounds , from billions of compounds in a chemical library including a recent study that targeted cannabinoid receptors (CB) and Rho associated coiled-coil containing protein kinase 1 (ROCK1) . However, VS methods use a static protein structure for hit identification and subsequent MD simulations are frequently needed to validate and refine the un-optimized protein–ligand interaction such as the protocol used by Mai et al’s study . The cosolvent-based simulations ,,− , have the advantage of accounting for the dynamic interaction between the protein and the ligand and allowing for reshaping the binding site induced by the ligands.…”

“…As an example in the VS approach, Mai et al recently constructed a pharmacophore model based on several key amino acids on IL33 that interact with ST2. Using the pharmacophore model and the virtual screening approach, they identified ZINC59514725 and suggested that ZINC59514725 may be more potent than iST2-1 through computational calculations.…”

Identification of small molecules as potential inhibitors of interleukin 6: a multi-computational investigation

“…Although the benefits obtained from monoclonal antibody treatment have been demonstrated, these biological agents still have certain disadvantages, such as high treatment cost, unsuitability for oral administration, difficulty to control, and the risk of inducing strong immune responses. Small molecule therapy, on the other hand, provides a number of significant advantages, including simpler oral administration, possible optimization of pharmacokinetic properties, lower treatment costs, more controllability, and less immunogenic [ 18 ]. Oral bioavailability offers significant benefits in terms of accessibility, compliance, and widespread use, making such therapy more suitable for long-term treatment.…”