Identification of APOE4 Modulators, Targeted Therapeutic Candidates in Coronary Artery Disease, Using Molecular Docking Studies

Abstract

Investigate the protein-ligand binding affinity and evaluate the receptor binding abilities of different classes of ligands for APOE4 through molecular docking studies. The polymorphic nature of human Apo E gene encodes one of 3 common epsilon (ε) alleles (ε2, ε3, and ε4), reported to influence the risk of cardiovascular diseases. Structural basis of APOE4 involvement in CAD suggests that the intramolecular domain interactions to be a suitable target for therapeutic intervention. Identification of APOE4 modulators, targeted towards therapeutic candidates in CAD using Molecular Docking studies. Various classes of ligands including known drugs used in the treatment of CAD, fragment-based stabilizers and their similar structures and molecules with known bioactivity against APOE4 were screened for their binding affinity and further investigated for their interactions with APOE4. Computational studies show the benzyl amide derived structures to be useful candidates in modulation of APOE4. The protein-ligand binding affinities predicted in the study indicated receptor binding abilities of APOE4 that can lead to have interesting insights on structural conformity of APOE4 and its correlated functional aspects. Understanding modulation of APOE4 can pave ways to use it as biomarker for CAD as well as for its therapeutics. Further analysis of the variation of the docked protein structure, molecular dynamic simulation can be performed to generate a dynamic structure for binding analysis.

Molecular docking analysis of arjunolic acid from Terminalia arjuna with a coronary artery disease target APOE4

“…The final model was selected based on the lower discrete optimized protein energy (DOPE) score which was -0.24 and was further was validated both on geometric and energetic scale using PROCHECK from PDBsum) and Discovery Studio. Model structure of APOE4 generated was further minimized using YASARA minimization server in presence of water as solvent to improve orientations [3].…”

“…Coronary artery disease (CAD) is a common heart condition that involves atherosclerotic plaque formation in the vessel lumen, leading to inadequate supply of blood and oxygen to the myocardium [1]. Apo lipoprotein-E (APOE) encoded by APOE gene, is a plasma glycoprotein of 34.15 kDa with 299-amino acids has revealed a pivotal role in the biological processes including CAD progression [2,3]. Studies discussed impairment of cholesterol efflux in CAD which has been linked to APOE4 accumulation in the endosomal compartments of the cells resulting in increased intracellular cholesterol production and atherosclerosis [4].…”

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

“…The targeted APOE4 protein structure included in this study had been modelled and validated both on geometric and energetic scale and also minimized in our previous study [23], whereas the APOE3 (2L7B) structure was retrieved from PDB database. The homology model built was submitted to Protein Model DataBase (http://srv00.recas.ba.infn.it/PMDB/main.php) and was assigned a PMDB ID: PM0084216 [24].…”