Molecular Drug Simulation and Experimental Validation of the CD36 Receptor Competitively Binding to Long-Chain Fatty Acids by 7-Ketocholesteryl-9-carboxynonanoate

Abstract

Long-chain fatty acids (LCFAs) are one of the main energy-supplying substances in the body. LCFAs with different lengths and saturations may have contrasting biological effects that exacerbate or alleviate progress against a variety of systemic disorders of lipid metabolism in organisms. Nonalcoholic fatty liver disease is characterized by chronic inflammation and steatosis, mainly caused by the ectopic accumulation of lipids in the liver, especially LCFAs. CD36 is a scavenger receptor that recognizes and mediates the transmembrane absorption of LCFAs and is expressed in a variety of cells throughout the body. In previous studies, our group found that 7-ketocholesteryl-9-carboxynonanoate (oxLig-1) has the biological effect of targeting CD36 to inhibit oxidized low-density lipoprotein lipotoxicity-induced lipid metabolism disorder; it has an ω-carboxyl physiologically active center and is structurally similar to LCFAs. However, the biological mechanism of oxLig-1 binding to CD36 and competing for binding to different types of LCFAs is still not clear. In this study, molecular docking and molecular dynamics simulation were utilized to simulate and analyze the binding activity between oxLig-1 and different types of LCFAs to CD36 and confirmed by the enzyme-linked immunosorbent assay (ELISA) method. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) platform was applied to predict the drug-forming properties of oxLig-1, and HepG2 cells model of oleic acid and nonalcoholic fatty liver disease (NAFLD) model mice were validated to verify the biological protection of oxLig-1 on lipid lowering. The results showed that there was a co-binding site of LCFAs and oxLig-1 on CD36, and the binding driving forces were mainly hydrogen bonding and hydrophobic interactions. The binding abilities of polyunsaturated LCFAs, oxLig-1, monounsaturated LCFAs, and saturated LCFAs to CD36 showed a decreasing trend in this order. There was a similar decreasing trend in the stability of the molecular dynamics simulation. ELISA results similarly confirmed that the binding activity of oxLig-1 to CD36 was significantly higher than that of typical monounsaturated and saturated LCFAs. ADMET prediction results indicated that oxLig-1 had a good drug-forming property. HepG2 cells model of oleic acid and NAFLD model mice study results demonstrated the favorable lipid-lowering biological effects of oxLig-1. Therefore, oxLig-1 may have a protective effect by targeting CD36 to inhibit the excessive influx and deposition of lipotoxicity monounsaturated LCFAs and saturated LCFAs in hepatocytes.

A Characterization and Functional Analysis of Peroxisome Proliferator-Activated Receptor Gamma Splicing Variants in the Buffalo Mammary Gland

“…The ACSL1 has been found to play key roles in the regulation of triglyceride synthesis by activating fatty acid, i.e., altering the free LCFAs to fatty acyl-CoA esters [ 28 ]. CD36 , also known as the scavenger receptor B2, is a key fatty acid sensor and regulator of lipid metabolism, which has a high affinity for long-chain fatty acids and can bind and transport them into cells [ 27 , 29 , 30 ]. Reports have found that the expression of CD36 was significantly increased in the lactation of cows, and the overexpression of CD36 increased the uptake of LCFAs in the mammary cells [ 31 ].…”

Computer-Aided Drug Design and Drug Discovery: A Prospective Analysis

“…However, if the simulation lacks crucial real-world data on external environmental factors or unexpected biological responses, the predictions may deviate significantly from the actual outcomes. These models, while sophisticated, often require experimental validation to ascertain their predictions [ 9 , 10 ]. In conclusion, CADD signifies the harmonious blend of biology and technology, aiming to expedite drug discovery.…”