title: Structure-based Design Targeted at LOX-1, a Receptor for Oxidized Low-Density Lipoprotein.
abstract: Atherosclerosis related cardiovascular diseases continue to be the primary cause of mortality in developed countries. The elevated level of low density lipoprotein (LDL) is generally considered to be the driver of atherosclerosis, but recent years have seen a shift in this perception in that the vascular plaque buildup is mainly caused by oxidized LDL (ox-LDL) rather than native-LDL. The scavenger receptor LOX-1 found in endothelial cells binds and internalizes ox-LDL which leads to the initiation of plaque formation in arteries. Using virtual screening techniques, we identified a few potential small molecule inhibitors of LOX-1 and tested their inhibitory potential using differential scanning fluorimetry and various cellular assays. Two of these molecules significantly reduced the uptake of ox-LDL by human endothelial cells, LOX-1 transcription and the activation of ERK1/2 and p38 MAPKs in human endothelial cells. In addition, these molecules suppressed ox-LDL-induced VCAM-1 expression and monocyte adhesion onto human endothelial cells demonstrating their therapeutic potential.
authors.affiliation: Department of Physiology and Biophysics College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Shraddha
authors.initials: S
authors.lastname: Thakkar
authors.affiliation: Department of Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Xianwei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Magomed
authors.initials: M
authors.lastname: Khaidakov
authors.affiliation: Department of Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Yao
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Department of Physiology and Biophysics College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Kuppan
authors.initials: K
authors.lastname: Gokulan
authors.affiliation: Department of Physiology and Biophysics College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.|Department of Medicine, College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Jawahar L
authors.initials: JL
authors.lastname: Mehta
authors.affiliation: Department of Physiology and Biophysics College of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
authors.forename: Kottayil I
authors.initials: KI
authors.lastname: Varughese
mesh_terms: D002448:Cell Adhesion / Q000235:genetics; D003198:Computer Simulation; D015195:Drug Design; D055808:Drug Discovery; D015870:Gene Expression; D005786:Gene Expression Regulation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008077:Lipoproteins, LDL / Q000737:chemistry*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D051127:Scavenger Receptors, Class E / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D008077:Lipoproteins, LDL; C495137:OLR1 protein, human; D051127:Scavenger Receptors, Class E; D054852:Small Molecule Libraries; D019010:Vascular Cell Adhesion Molecule-1; C099252:oxidized low density lipoprotein; D020928:Mitogen-Activated Protein Kinases