Small Molecule Inhibitors Targeting Endothelial IL-1β Receptor (IL-1R1): A Novel Approach to Atherosclerosis Therapy

Abstract

The current study identified small molecule inhibitors targeting IL-1β receptor in inhibiting the atherosclerosis. IL-1β plays an important role in the progression of atherosclerosis by binding to the IL-1R1 receptor. IL-1β secreted by the macrophage induces the expression of cell adhesion molecules on the endothelial cell which causes recruitment of immune cells to the intimal site, promoting the atherosclerosis progression. It also releases IL-6 and MMPs which helps in thrombus formation. Thus, targeting IL-1β can help in limiting the recruitment of immune cell to the intimal site. IL-1RA is an antagonist which binds to the IL-1R1 receptor and limit its interaction with the IL-1β. Thus, critical residues on the IL-1R1 interacting with both the IL-1β and IL-1RA were analyzed. A total of 17 residues were found to be common between both the complexs in the 4A region. Further, in-vitro study suggests 12 critical residues on the IL-1R1 mediating the interaction with the IL-1β. Thus, small molecule inhibitors were used to target the critical residues on the IL-1R1 receptor binding with the IL-1β. Virtual screening in Schrodinger and Auto Dock Vina suggested six compounds interacting with most of the critical residues on the IL-1R1 receptor. Further, physicochemical and ADMET analysis of those compounds suggested good values in all the parameters. Thus, the screened compounds hold good potential to act as an anti-IL-1β inhibitor in limiting the progression of atherosclerosis. Further studies would be to check the efficacy and effectivity of the compounds at the in-vitro and in-vivo levels.