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

Yıl 2024, Cilt: 3 Sayı: 4, 134 - 144

Zekeriya Düzgün , Birgül Kural , Asım Örem , İlkay Yıldız

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

Öz

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.

Anahtar Kelimeler

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

Öz

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.

Anahtar Kelimeler

Cardiovascular disease, Lipid-lowering drugs, Molecular docking, Paraoxonase-1 (PON1), PON1 polymorphisms

Etik Beyan

Ethical approval was not required for this study.

Teşekkür

The numerical calculations reported in this paper were partially performed at TUBITAK ULAKBIM, High Performance and Grid Computing Center (TRUBA resources).

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