Computational Studies and Scaffold Search for APOE4 as Coronary Artery Disease Target by Virtual Screening

Abstract

Apolipoprotein E (APOE) polymorphism is involved in the pathogenesis of atherosclerosis and conveys a higher risk of coronary artery disease (CAD). The structural features of the isoforms (APOE2, APOE3, and APOE4) differ by only single amino acid that explicate their unique functions as lipid transporter with a role in cholesterol metabolism. It is therefore hypothesized that the cysteine/arginine change at position 112 results in structural differences within APOE3 and APOE4 leading to variation in binding affinities of ligands. We report for the first time computational and structural studies that reveal selectivity amongst ligands for APOE binding, with possible links to CAD pathogenesis. Molecular dynamics study allowed to understand the APOE conformational flexibility and its stability followed by Molecular docking studies that identified scaffold of Ligand 11802 by screening of 22,203 molecules from ChemDiv Library which showed the highest affinity towards APOE4. The ligand showed the presence of chemical moieties, similar to that present in known APOE4 stabilizers in Alzheimer’s Disease, which opened a possibility for the ligand as a potential therapeutic agent that could affect the behaviour of APOE4 in CAD pathogenesis. Further, ligand-binding preferences of each isoform with LDL receptors (LDLR) allowed understanding of the in-vivo mechanism in CAD pathogenesis.