Exploring the druggability of oxidized low-density lipoprotein (ox-LDL) receptor, LOX-1, a proatherogenic drug target involved in atherosclerosis.

Lectin-like oxidized low-density lipoprotein (ox-LDL) receptor 1 (LOX-1) is a vital scavenger receptor involved in ox-LDL binding, internalization, and subsequent proatherogenic signaling leading to cellular dysfunction and atherosclerotic plaque formation. Existing data suggest that modulation of ox-LDL - LOX-1 interaction can prevent or slow down atherosclerosis. Therefore, we utilized computational methods such as multi-solvent simulation and characterized two top-ranked druggable sites. Using systematic molecular docking followed by atomistic molecular dynamics simulation, we have identified and shortlisted small molecules from the NCI library that target two key binding sites. We demonstrate, using surface plasmon resonance (SPR), that four of the shortlisted molecules bind one-on-one to the purified C-terminal domain (CTLD) of LOX-1 receptor with high affinity (K), ranging from 4.9 nM to 20.1 μM. Further, we performed WaterMap analysis to understand the role of individual water molecules in small molecule binding and the LOX-1-ligand complex stability. Our data clearly show that LOX-1 is druggable with small molecules. Our study provides strategies to identify novel inhibitors to attenuate ox-LDL - LOX-1 interaction.