Structure guided inhibitor discovery targeting a membrane receptor involved in atherosclerosis
Arockiasamy Arulandu1, Akanksha Tomar1, Azeem Khan1, Sibasis Sahoo1, Muthu Sankar Aathi1, Shobhan Kuila1, Anmol Chandele1, Jawahar L Mehta2, Kottayil I Varughese3
1International Centre for Genetic Engineering and Biotechnology, New Delhi, India; 2University of Arkansas for Medical Sciences and the Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, United States; 3University of Arkansas for Medical Sciences, Little Rock, Arkansas, United States.
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
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