Molecular docking analysis of the affinities of lipid-lowering drugs to paraoxonase-1 enzyme and its polymorphic structures

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Paraoxonase-1 (PON1) is a high-density lipoprotein (HDL)-associated enzyme that exhibits paraoxonase, arylesterase, and lactonase activities. This multifunctional enzyme plays a crucial role in preventing atherosclerosis by inhibiting low-density lipoprotein (LDL) oxidation and reducing oxidized lipid levels. The present study aimed to investigate the affinities of various lipid-lowering drugs to PON1 and its polymorphic structures [(M/L)55 and (Q/R)192] using advanced molecular docking methods. The research utilized a comprehensive computational approach, including homology modeling, molecular dynamics simulation, and AutoDock 4 software to analyze the interactions between PON1 and several classes of lipid-lowering agents. These included statins (simvastatin, atorvastatin, lovastatin, mevastatin, fluvastatin, rosuvastatin, pravastatin), fibrates (fenofibrate, gemfibrozil, bezafibrate, ciprofibrate), niacin, ezetimibe, orlistat, sibutramine, probucol, and phytosterols (brassicasterol, campesterol, β-sitosterol, stigmasterol). The study revealed varying affinities of these drugs to PON1 and its polymorphic structures. Notably, brassicasterol showed the highest affinity for the normal PON1 structure, while sibutramine and stigmasterol demonstrated the highest affinities for the Q/R 192 and M/L 55 polymorphic structures, respectively. Conversely, orlistat exhibited the lowest affinity for both normal PON1 and the M/L 55 polymorphic structure, while atorvastatin showed the lowest affinity for the Q/R 192 polymorphic structure. These findings provide valuable insights into the potential interactions between lipid-lowering drugs and PON1, suggesting that consideration of PON1 affinity might be important in the selection of lipid-lowering therapies, particularly in individuals with different PON1 polymorphisms. However, further in vitro and in vivo studies are necessary to validate these computational results and establish their clinical relevance.