DOĞAL ALFA-GLUKOSİDAZ İNHİBİTÖRLERİNİ ANLAMAYA DOĞRU: HESAPLAMALI BİR ÇALIŞMA

Öz

Amaç: Şeker hastalığı dünya çapında yüz milyonlarca insanı etkileyen metabolik bir hastalıktır. Hastalık yetersiz insülin üretimi veya insülin direncinden kaynaklanan bozulmuş glukoz homeostazisinin neden olduğu hiperglisemi ile karakterizedir. Yemek sonrası kan şekeri seviyesini düşürmek amacıyla klinikte kullanılan α-glukosidaz inhibitörü ilaçlar bulunmaktadır. Ancak bu ilaçların yan etkileri olduğundan daha az yan etkili ve yüksek etkinliği olan yeni α-glukosidaz inhibitörlerinin keşfedilmesine ihtiyaç duyulmaktadır. Şeker hastalığıyla mücadelede doğal kaynaklı ürünlerin kullanımına olan ilgi giderek artmaktadır. Bu nedenle doğal kaynaklı α-glukosidaz inhibitörlerinin enzimi inhibe etme potansiyelleri hesaplamalı yöntemlerle araştırılmıştır. Gereç ve Yöntem: Seçilmiş doğal kaynaklı α-glukosidaz inhibitörlerinin bağlanma potansiyeli, moleküler doking yoluyla araştırılmıştır. Daha sonra, en yüksek bağlanma potansiyeline sahip komplekslerin stabilitesi moleküler dinamik (MD) simülasyonu yoluyla değerlendirilmiştir. Sonuç ve Tartışma: Moleküler doking çalışması bileşik 2'nin standart ilaç olan akarbozdan daha iyi bağlanma potansiyeline sahip olduğunu göstermiştir. Bileşik 7 ise standart ilaca benzer bağlanma potansiyeline sahipti. Ayrıca, test edilen bileşiklerin hepsi enzime karşı makul bağlanma potansiyeli sergilemelerine rağmen standart ilaçtan daha zayıf bağlandığı görülmüştür. MD simülasyonu da bileşik 2 ve 7'nin standart ilaca benzer stabiliteye sahip kompleksler verdiğini göstermiştir. Hesaplama yöntemlerin sonuçları araştırılan doğal kaynaklı inhibitörlerin enzime bağlanma yeteneğine sahip olduğunu ve stabil kompleksler oluşturduğunu ortaya çıkarmıştır. Bu nedenle bu bileşikler klinik kullanım için potansiyel α-glukosidaz inhibitörleri olabilir. Bu yüzden en yüksek bağlanma potansiyeline sahip bileşikler üzerinde daha fazla in vitro araştırma yapılması tavsiye edilir.

Anahtar Kelimeler

• Diyabet
• doğal inhibitörler
• α-glukosidaz
• MD simülasyon
• moleküler doking

TOWARDS UNDERSTANDING NATURAL ALPHA-GLUCOSIDASE INHIBITORS: A COMPUTATIONAL STUDY

Öz

Objective: Diabetes mellitus is a metabolic disorder affecting hundreds of millions of people around the world. It is characterized by hyperglycemia caused by impaired glucose homeostasis that results from insufficient insulin production or insulin resistance. There are clinically available α-glucosidase inhibitor drugs that are used to decrease postprandial blood glucose level. However, these drugs have side effects that necessitated the discovery of new α-glucosidase inhibitors with less side effects and high potency. The interest in the use of natural products to deal with diabetes has been increasing. Therefore, the potential of natural α-glucosidase inhibitors to inhibit the enzyme was investigated through computational methods. Material and Method: The binding potential of selected natural α-glucosidase inhibitors was investigated through molecular docking. Thereafter, the stability of the complexes with the highest binding potential were assessed through molecular dynamics (MD) simulation. Result and Discussion: The molecular docking demonstrated that compound 2 had better binding potential than the standard drug, acarbose. Compound 7 had comparable binding potential to the standard drug. Furthermore, all the tested compounds exhibited a reasonable binding potential towards the enzyme but were weaker than the standard drug. The MD simulation demonstrated that compounds 2 and 7 gave complexes with similar stability to the standard drug. The overall computational results revealed that the natural inhibitors investigated had the ability to bind to the enzyme and formed stable complexes. Therefore, these compounds could be potential α-glucosidase inhibitors for clinical use. For this reason, further in vitro investigations on compounds with the highest binding potential is recommended.

Anahtar Kelimeler

• Diabetes
• α-glucosidase
• MD simulation
• molecular docking
• natural inhibitors

Teşekkür

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

Kaynakça

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