Molecular docking analysis of the affinities of lipid-lowering drugs to paraoxonase-1 enzyme and its polymorphic structures
Abstract
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.
Keywords
Cardiovascular disease, Lipid-lowering drugs, Molecular docking, Paraoxonase-1 (PON1), PON1 polymorphisms
Ethical Statement
Ethical approval was not required for this study.
Thanks
The numerical calculations reported in this paper were partially performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources).
References
- Durrington PN, Bashir B, Soran H. Paraoxonase 1 and atherosclerosis. Front Cardiovasc Med. 2023;10:1065967.
- Dornas W, Silva M. Modulation of the antioxidant enzyme paraoxonase-1 for protection against cardiovascular diseases. Nutr Metab Cardiovasc Dis. 2024;34(12):2611-2622. doi:10.1016/j.numecd.2024.04.005
- Nasreen FJ, Balasubramaniam G. Paraoxonase gene polymorphisms: Understanding the biochemical and genetic basis of coronary artery disease. J Taibah Univ Med Sci. 2023;18(2):257-264.
- Hsu HY, Lin CJ, Lee YS, Wu TH, Chien KL. Efficacy of more intensive lipid-lowering therapy on cardiovascular diseases: a systematic review and meta-analysis. BMC Cardiovasc Disord. 2020;20:1-12.
- Godbole C, Thaker S, Salagre S, Shivane V, Gogtay N, Thatte U. A prospective study to assess the role of paraoxonase 1 genotype and phenotype on the lipid-lowering and antioxidant activity of statins. Indian J Pharmacol. 2023;55(3):179-184.
- Zaragoza-García O, Guzmán-Guzmán IP, Moreno-Godínez ME, et al. PON-1 haplotype (-108C> T, L55M, and Q192R) modulates the serum levels and activity PONase promoting an atherogenic lipid profile in rheumatoid arthritis patients. Clin Rheumatol. 2021;40:741-752.
- Muhammed MT, Aki-Yalcin E. Molecular docking: principles, advances, and its applications in drug discovery. Lett Drug Des Discov. 2024;21(3):480-495.
- Halgren TA. Merck molecular force field. I. Basis, form, scope, parameterization, and performance of MMFF94. J Comput Chem. 1996;17(5‐6):490-519.
- Gasteiger J, Marsili M. Iterative partial equalization of orbital electronegativity—a rapid access to atomic charges. Tetrahedron. 1980;36(22):3219-3228. doi:10.1016/0040-4020(80)80168-2
- Morris GM, Huey R, Olson AJ. Using autodock for ligand‐receptor docking. Curr Protoc Bioinforma. 2008;24(1):8-14.