Structure-guided inhibitor discovery targeting a membrane receptor involved in atherosclerosis

Atherosclerosis is a major cause of cardiovascular diseases and stroke.Oxidized low-density lipoprotein (Ox-LDL) plays a key role in the initiation and progression atherogenic process.Lectin-like ox-LDL receptor-1 (LOX-1) [1], a scavenger receptor present on vascular endothelial cells, macrophages, smooth muscle cells, and platelets, facilitates internalization of ox-LDL leading to atherosclerotic plaque formation.Existing data points towards LOX-1 as a potential target for novel anti-atherosclerosis therapy [2-3].However, no approved therapeutics targeting LOX-1 are known.Using computational tools, we first identified a potential druggable site on the extracellular C-terminal domain (CTLD) of LOX-1.Then, using structure-based screening and molecular dynamics we have identified and short-listed molecules from chemical libraries for further validation with a combination of surface plasmon resonance, cell-based ox-LDL uptake assay and complex crystal structures.Our data clearly shows that LOX-1 is druggable.Further studies will be performed to decipher mechanistic details of ox-LDL uptake inhibition.