Tip 2 Diyabet ile İlişkili İnsülin, Glukokortikoid ve GLP-1 Reseptörleri ile Doğal Bileşik Zeaksantinin Etkileşiminin in Silico Değerlendirmesi

Abstract

Tip 2 diabetes mellitus (T2DM), pankreas β-hücre disfonksiyonuna bağlı periferik dokularda insülin direnci nedeniyle gelişen, kalıcı hiperglisemi ile karakterize kronik metabolik bozukluktur. Bu patolojik durum, insülin sinyalleme kaskadlarının bozulması, glukokortikoid ve GLP-1 reseptörlerine uygulanan metabolik stres ve glikoz homeostazının bozulması ile ilişkilidir. Bu çalışmada, mikroalgler gibi doğal kaynaklardan ekstrakte edilen karotenoid pigment zeaksantinin, T2DM ile ilişkili insülin, glukokortikoid ve GLP-1 hedef reseptörleri üzerindeki etkileşim potansiyeli, siliko moleküler modelleme yaklaşımları kullanılarak değerlendirilmiştir. Seçili glukokortikoid, insülin ve GLP-1 reseptörleri için zeaksantin bağlanma afiniteleri, yapısal olarak benzer doğal biyoaktif bileşikler ve sentetik inhibitörlerle karşılaştırmalı olarak moleküler yerleştirme yöntemi kullanılarak hesaplanmıştır. Zaman içinde en iyi konformasyona ulaşan reseptör-ligand komplekslerinin yapısal kararlılığını değerlendirmek için moleküler dinamik simülasyonları gerçekleştirilmiştir. Zeaksantin, INSR, GR ve GLP1'de sırasıyla -9,9, -6.1 ve -8.4 kcal/mol bağlanma enerjileri 30 Å grid size da göstermiştir. Benzer şekilde, zeaksantine yapısal olarak benzeyen diğer ligandların bağlanma afiniteleri sentetik inhibitörlerle karşılaştırılabilir düzeyde olup, daha güçlü bağlanma etkileşimleri sergileyerek zeaksantinin biyolojik potansiyelini desteklemektedir. Bulgularımız, doğal zeaksantinin kronik T2DM'de alternatif tedavi stratejileri için çok yönlü, hedef odaklı doğal bir ajan olarak potansiyelini vurgulamaktadır. Bu çalışma kapsamında zeaksantinin insülin direncini azaltma potansiyelini gösteren bulgularla paralel olarak, ön sonuçlarımız zeaksantini, T2DM'de alternatif tedavi stratejilerinde insülin duyarlılığını artıran ve glikoz homeostazını düzenleyen çok hedefli doğal kökenli umut vadeden öncü bir bileşik olabileceği öngörülmektedir.

Keywords

• Zeaksantin
• T2DM
• mikroalg
• doğal tedavi edici ajan
• tedavi
• moleküler modelleme

In silico Assessment of the Interaction of the Natural Compound Zeaxanthin with Insulin, Glucocorticoid, and GLP-1 Receptors Associated with Type 2 Diabetes

Abstract

Type 2 diabetes mellitus (T2DM), developing because of insulin resistance in peripheral tissues due to pancreatic β-cell dysfunction, chronic metabolic disorder characterized by persistent hyperglycaemia. This pathological state is associated with the impairment of insulin signalling cascades, along with metabolic stress imposed on glucocorticoid and GLP-1 receptors and the perturbation of glucose homeostasis. In this study, interaction potential of the carotenoid pigment zeaxanthin, extracted from natural origins such as microalgae, on insulin, glucocorticoid, and GLP-1 target receptors associated with T2DM was evaluated by employing in silico molecular modelling approaches. Zeaxanthin binding affinities for selected glucocorticoid, insulin, and GLP-1 receptors were computed using the molecular docking method, in comparison with structurally similar natural bioactive compounds and synthetic inhibitors. Molecular dynamics simulations were performed to assess the structural stability of the receptor–ligand complexes that achieved the best conformation over time. Zeaxanthin demonstrated binding energies of -9.9, -6.1 and -8.4 kcal/mol in the INSR, GR, and GLP1, respectively, at a grid size of 30 Å. Similarly, the binding affinities of other ligands structurally analogous to zeaxanthin were comparable to synthetic inhibitors and exhibited stronger binding interactions, supporting zeaxanthin's biological potential. Our findings highlight the potential of natural zeaxanthin as a versatile, targeted natural agent for alternative therapeutic strategies in chronic T2DM. In line with the findings demonstrating zeaxanthin’s potential to reduce insulin resistance within the scope of this study, our preliminary results suggest that zeaxanthin represents a promising lead compound of natural origin with multi-target activity, capable of enhancing insulin sensitivity and regulating glucose homeostasis as part of alternative treatment strategies for T2DM.

Keywords

• Zeaxanthin
• T2DM
• microalgae
• natural therapeutic agent
• treatment
• molecular modelling

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