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.
Steel bridge structure without intermediate bracing system (IBS) has been widely used in several countries and one of them is Japan. In this type of structure, the main steel girder is not reinforced by the stiffeners. The stiffness of the main girder is enhanced with steel plate directly welded to the top flange of the main girder, forming the “beams–system”. The reinforced concrete deck slab with the set of main girder and steel plate works compositely through steel shear connectors whose shape is C (channel) or I character. As for steel bridge structures, the main role of shear connectors is shear resistance between the concrete deck slab and steel girder plate in the exploitation stage. However, previous research has shown that the density of shear connectors influences on the stability as well as the stiffness of the bridge structure. Therefore, it has approved that this appurtenance is able to not only have the ability of shear resistance but also enhance the stiffness of the steel bridge structure which is particularly surveyed with the type of especial bridge structure – the steel bridge structure without IBS. Hence, the shear connectors in this kind of bridge structure are deliberately researched as an extra role in the construction stage. The following factors of the channel shape shear connectors would be researched for evaluating their impacting level on the stability of the special steel bridge structure: the properties (the length and the moment of inertia of the cross-section) and the density on the steel plate. Through the analysis of impacting level to the stability of three mentioned factors (the length and density of the shear connectors; the moment of inertia of the cross-section), the expected result is as following: 1) The minimum density of shear connectors is proposed. 2) The influence of the moment of inertia of the cross-section, the density, and the length on the stability is quite clear. 3) As for the economy, the optimal designed range among three factors is also suggested.
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