Lipid düşürücü ilaçların paraoksonaz-1 enzimine ve polimorfik yapılarına afinitelerinin moleküler docking analizi

Year 2024, Volume: 3 Issue: 4, 134 - 144

Zekeriya Düzgün , Birgül Kural , Asım Örem , İlkay Yıldız

https://doi.org/10.59518/farabimedj.1580265

Abstract

Paraoksonaz-1 (PON1), paraoksonaz, arilesteraz ve laktonaz aktiviteleri gösteren, yüksek yoğunluklu lipoprotein (HDL) ile ilişkili bir enzimdir. Bu çok fonksiyonlu enzim, düşük yoğunluklu lipoprotein (LDL) oksidasyonunu önleyerek ve oksitlenmiş lipid seviyelerini azaltarak aterosklerozun önlenmesinde önemli bir rol oynamaktadır. Bu çalışma, çeşitli lipid düşürücü ilaçların PON1 ve polimorfik yapılarına [(M/L)55 ve (Q/R)192] olan afinitelerini gelişmiş moleküler doking yöntemleri kullanarak araştırmayı amaçlamıştır. Araştırma, PON1 ile çeşitli lipid düşürücü ajanlar arasındaki etkileşimleri analiz etmek için homoloji modellemesi, moleküler dinamik simülasyonu ve AutoDock 4 yazılımını içeren kapsamlı bir hesaplamalı yaklaşım kullanmıştır. Bu ajanlar arasında statinler (simvastatin, atorvastatin, lovastatin, mevastatin, fluvastatin, rosuvastatin, pravastatin), fibratlar (fenofibrat, gemfibrozil, bezafibrat, siprofibrat), niasin, ezetimib, orlistat, sibutramin, probukol ve fitosteroller (brasikasterol, kampesterol, β-sitosterol, stigmasterol) yeralmaktadır. Çalışma, builaçların PON1 ve polimorfik yapılarına değişen afiniteler gösterdiğini ortaya koymuştur. Özellikle, brasikasterol normal PON1 yapısına en yüksek afiniteyi gösterirken, sibutramin ve stigmasterol sırasıyla Q/R 192 ve M/L 55 polimorfik yapılarına en yüksek afiniteleri göstermiştir. Buna karşılık, orlistat hem normal PON1 hem de M/L 55 polimorfik yapısına en düşük afiniteyi gösterirken, atorvastatin Q/R 192 polimorfik yapısına en düşük afiniteyi göstermiştir. Bu bulgular, lipid düşürücü ilaçlar ile PON1 arasındaki potansiyel etkileşimler hakkında değerli bilgiler sağlamakta ve PON1 afinitesinin, özellikle farklı PON1 polimorfizmleri olan bireylerde lipid düşürücü tedavilerin seçiminde önemli olabileceğini göstermektedir. Bununla birlikte, bu hesaplamalı sonuçları doğrulamak ve klinik önemini belirlemek için daha fazla in vitro ve in vivo çalışma gereklidir.

Keywords

Kardiyovasküler hastalık, Lipid düşürücü ilaçlar, Moleküler doking, Paraoksonaz-1 (PON1), PON1 polimorfizmleri

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.
• Duzgun Z, Kural BV, Orem A, Yildiz I. In silico investigation of the interactions of certain drugs proposed for the treatment of Covid-19 with the paraoxonase-1. J Biomol Struct Dyn. 2023;41(3):884-896.
• Pronk S, Páll S, Schulz R, et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013;29(7):845-854.
• Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility. J Comput Chem. 2009;30(16):2785-2791.
• Trott O, Olson AJ. AutoDock Vina: improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. J Comput Chem. 2010;31(2):455-461.
• Ben-David M, Elias M, Filippi JJ, et al. Catalytic versatility and backups in enzyme active sites: The case of serum paraoxonase 1. J Mol Biol. 2012;418(3-4):181-196. doi:10.1016/j.jmb.2012.02.042
• Pettersen EF, Goddard TD, Huang CC, et al. UCSF Chimera--A visualization system for exploratory research and analysis. J Comput Chem. 2004;25(13):1605-1612. doi:10.1002/jcc.20084
• Consortium U. UniProt: a worldwide hub of protein knowledge. Nucleic Acids Res. 2019;47(D1):D506-D515.
• Webb B, Sali A. Comparative protein structure modeling using MODELLER. Curr Protoc Bioinforma. 2016;54(1):5-6.
• Chen VB, Arendall WB, Headd JJ, et al. MolProbity: all-atom structure validation for macromolecular crystallography. Acta Crystallogr Sect D Biol Crystallogr. 2010;66(1):12-21. doi:10.1107/S0907444909042073
• Pronk S, Pall S, Schulz R, et al. GROMACS 4.5: a high-throughput and highly parallel open source molecular simulation toolkit. Bioinformatics. 2013;29(7):845-854. doi:10.1093/bioinformatics/btt055
• Lindorff‐Larsen K, Piana S, Palmo K, et al. Improved side‐chain torsion potentials for the Amber ff99SB protein force field. Proteins Struct Funct Bioinforma. 2010;78(8):1950-1958.
• Zielkiewicz J. Structural properties of water: Comparison of the SPC, SPCE, TIP4P, and TIP5P models of water. J Chem Phys. 2005;123(10).
• Damm KL, Carlson HA. Gaussian-weighted RMSD superposition of proteins: a structural comparison for flexible proteins and predicted protein structures. Biophys J. 2006;90(12):4558-4573.
• Ramachandran S, Dokholyan N V. Homology modeling: generating structural models to understand protein function and mechanism. In: Computational Modeling of Biological Systems: From Molecules to Pathways. Springer; 2012:97-116.
• Levitt M, Sharon R. Accurate simulation of protein dynamics in solution. Proc Natl Acad Sci. 1988;85(20):7557-7561.
• Hu X, Jiang X, Lenz DE, Cerasoli DM, Wallqvist A. In silico analyses of substrate interactions with human serum paraoxonase 1. Proteins Struct Funct Bioinforma. 2009;75(2):486-498.
• Adcock SA, McCammon JA. Molecular dynamics: survey of methods for simulating the activity of proteins. Chem Rev. 2006;106(5):1589-1615.
• Hornak V, Abel R, Okur A, Strockbine B, Roitberg A, Simmerling C. Comparison of multiple Amber force fields and development of improved protein backbone parameters. Proteins Struct Funct Bioinforma. 2006;65(3):712-725.
• Hu X, Jiang X, Lenz DE, Cerasoli DM, Wallqvist A. In silico analyses of substrate interactions with human serum paraoxonase 1. Proteins Struct Funct Bioinforma. 2009;75(2):486-498. doi:10.1002/prot.22264
• Harel M, Aharoni A, Gaidukov L, et al. Structure and evolution of the serum paraoxonase family of detoxifying and anti-atherosclerotic enzymes. Nat Struct Mol Biol. 2004;11(5):412-419.
• Yeung DT, Josse D, Nicholson JD, et al. Structure/function analyses of human serum paraoxonase (HuPON1) mutants designed from a DFPase-like homology model. Biochim Biophys Acta (BBA)-Proteins Proteomics. 2004;1702(1):67-77.
• Kural BV, Örem C, Uydu HA, Alver A, Örem A. The effects of lipid-lowering therapy on paraoxonase activities and their relationships with the oxidant–antioxidant system in patients with dyslipidemia. Coron Artery Dis. 2004;15(5):277-283.
• Abdin AA, Hassanien MA, Ibrahim EA, Abou El SEDA. Modulating effect of atorvastatin on paraoxonase 1 activity in type 2 diabetic Egyptian patients with or without nephropathy. J Diabetes Complications. 2010;24(5):325-333.
• Harangi M, Seres I, Varga Z, et al. Atorvastatin effect on high-density lipoprotein-associated paraoxonase activity and oxidative DNA damage. Eur J Clin Pharmacol. 2004;60:685-691.
• Oranje WA, Sels JPJE, Rondas-Colbers GJWM, Lemmens PJMR, Wolffenbuttel BHR. Effect of atorvastatin on LDL oxidation and antioxidants in normocholesterolemic type 2 diabetic patients. Clin Chim acta. 2001;311(2):91-94.
• Bergheanu SC, Van Tol A, Dallinga-Thie GM, et al. Effect of rosuvastatin versus atorvastatin treatment on paraoxonase-1 activity in men with established cardiovascular disease and a low HDL-cholesterol. Curr Med Res Opin. 2007;23(9):2235-2240.
• Audikovszky M, Pados G, Seres I, et al. Orlistat increases serum paraoxonase activity in obese patients. Nutr Metab Cardiovasc Dis. 2007;17(4):268-273.
• Billecke S, Draganov D, Counsell R, et al. Human serum paraoxonase (PON1) isozymes Q and R hydrolyze lactones and cyclic carbonate esters. Drug Metab Dispos. 2000;28(11):1335-1342.
• Gouédard C, Koum-Besson N, Barouki R, Morel Y. Opposite regulation of the human paraoxonase-1 gene PON-1 by fenofibrate and statins. Mol Pharmacol. 2003;63(4):945-956.
• Tomás M, Sentí M, García-Faria F, et al. Effect of simvastatin therapy on paraoxonase activity and related lipoproteins in familial hypercholesterolemic patients. Arterioscler Thromb Vasc Biol. 2000;20(9):2113-2119.
• Ferretti G, Bacchetti T, Sahebkar A. Effect of statin therapy on paraoxonase-1 status: a systematic review and meta-analysis of 25 clinical trials. Prog Lipid Res. 2015;60:50-73.
• Yi GH, Mo ZC, Ye YP, et al. Effects of probucol on paraoxonase 1 expression and oxidative stress in hyperlipidemic mice. Cell Biol Int. 2008;32(3):S19-S20.
• Kim DS, Burt AA, Ranchalis JE, et al. Dietary cholesterol increases paraoxonase 1 enzyme activity. J Lipid Res. 2012;53(11):2450-2458.
• Sutherland WHF, Robertson MC, Williamson SA, Nye ER. Plasma noncholesterol sterols in male distance runners and sedentary men. Eur J Appl Physiol Occup Physiol. 1991;63:119-123.
• Zak A, Zeman M, Vitkova D, Hrabak P, Tvrzicka E. Beta-sitosterol in the treatment of hypercholesterolemia. Cas Lek Cesk. 1990;129(42):1320-1323.
• Yesilbursa D, Serdar A, Saltan Y, et al. The effect of fenofibrate on serum paraoxonase activity and inflammatory markers in patients with combined hyperlipidemia. Polish Hear J (Kardiologia Pol. 2005;62(6):530.
• Macan M, Vrkić N, Lucić Vrdoljak A, Radić B, Bradamante V. Effects of high sucrose diet, gemfibrozil, and their combination on plasma paraoxonase 1 activity and lipid levels in rats. Acta Biochim Pol. 2010;57(3):321-326.
• Durrington PN, Mackness MI, Bhatnagar D, et al. Effects of two different fibric acid derivatives on lipoproteins, cholesteryl ester transfer, fibrinogen, plasminogen activator inhibitor and paraoxonase activity in type IIb hyperlipoproteinaemia. Atherosclerosis. 1998;138(1):217-225.
• Tang WH, Villines T, Hazen S, et al. Effect of niacin and ezetimibe on serum paraoxonase and arylesterase activities of HDL cholesterol. J Am Coll Cardiol. 2012;59(13S):E1497-E1497.
• James WPT, Astrup A, Finer N, et al. Effect of sibutramine on weight maintenance after weight loss: a randomised trial. Lancet. 2000;356(9248):2119-2125.