The role of antibiotics in the management of the polyol pathway: An In Vitro and In Silico approach Poliol yolunun antibiyotikler yoluyla kontrolü: Bir in vitro ve in siliko yaklaşım

Abstract

Abstract Increased activity of aldose reductase (AR) and sorbitol dehydrogenase (SDH) are the major causes of diabetic complications. Thus, inhibition of these two enzymes is vital in preventing diabetic complications. As the synthesis of new and effective AR and SDH enzyme inhibitors is quite difficult, we have investigated the inhibition effects of antibiotics, which are already widely used in medicine, on AR and SDH enzymes. AR and SDH enzymes were purified from bovine kidney, in vitro effects of antibiotics on enzymes were determined, and molecular docking simulations were carried out to understand inhibition mechanisms. The antibiotics ampicillin and amikacin inhibited both AR and SDH enzymes at very low concentrations. The best inhibitors for AR were found to be ceftriaxone, tylosin, and metronidazole with IC50 values of 28.75 µM, 49.28 µM and 58.42 µM, respectively. The best inhibitors for SDH were seen to be amikacin, ampicillin, and ceftazidime with IC50 values of 2.4 mM, 2.62 mM, and 3.76 mM, respectively. The results of inhibition and docking studies showed that antibiotics are highly effective on these enzymes. The results obtained can be used as a reference for synthesizing better inhibitors in future studies. Öz Aldoz redüktaz (AR) ve sorbitol dehidrogenazın (SDH) artan aktivitesi, diyabetik komplikasyonların başlıca nedenleridir. Bu nedenle, bu iki enzimin inhibisyonu, diyabetik komplikasyonların önlenmesinde hayati önem taşımaktadır. Çalışmamızda, yeni ve etkili AR ve SDH enzim inhibitörlerinin sentezi oldukça zor olduğundan, halihazırda tıpta yaygın olarak kullanılan antibiyotiklerin AR ve SDH enzimleri üzerindeki inhibisyon etkileri araştırılmıştır. AR ve SDH enzimleri sığır böbreğinden saflaştırılmış, antibiyotiklerin enzimler üzerindeki in vitro etkileri belirlenmiş ve inhibisyon mekanizmalarının aydınlatılması amacıyla moleküler docking simülasyonları gerçekleştirilmiştir. Ampisilin ve amikasin antibiyotikleri hem AR hem de SDH enzimlerini çok düşük konsantrasyonlarda inhibe etmiştir. AR için en iyi inhibitörlerin sırasıyla 28.75 µM, 49.28 µM ve 58.42 µM IC50 değerleri ile seftriakson, tylosin ve metronidazol antibiyotikleri olduğu bulunmuştur. En iyi SDH inhibitörlerinin sırasıyla 2,4 mM, 2,62 mM ve 3,76 mM IC50 değerleri ile amikasin, ampisilin ve seftazidim olduğu görülmüştür. İnhibisyon ve docking çalışmalarının sonuçları, antibiyotiklerin bu enzimler üzerinde oldukça etkili olduğunu göstermiştir. Elde edilen sonuçlar, gelecekteki çalışmalarda daha iyi inhibitörlerin sentezlenmesi için referans olarak kullanılabileceği düşünülmektedir.

Keywords

• aldose reductase
• molecular docking
• polyol pathway
• sorbitol dehydrogenase
• aldoz redüktaz
• moleküler docking
• poliol yolu
• sorbitol dehidrogenaz

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