Nipagin Türevi Yeni Hidrazonların Sentezi ve in Siliko Biyolojik Etkinliklerinin Belirlenmesi

Öz

Bu çalışmada nipagin’den (metil paraben, metil-4-hidroksibenzoat) hareketle yeni seçici ve düşük toksisiteye sahip potansiyel anti kanser ajanlar geliştirilmesi amacıyla arilidenhidrazid yapısında sekiz adet bileşik (4-11) sentezlendi ve bu bileşiklerin meme kanseri büyüme faktörü reseptörü olan HER2’ye karşı etkinlikleri in siliko yöntemlerle ilk defa araştırıldı. Öncelikle moleküler docking çalışmaları ile hedef bileşiklerin ilgili protein üzerindeki bağlanma skorları ve serbest bağlanma enerjileri belirlendi, daha sonra moleküler dinamik çalışmaları ile protein-ligand komplekslerinin kararlılıkları incelendi ve son olarak bileşiklerin tahmini ADME parametreleri hesaplandı. Sentezlenen bütün bileşikler 1H NMR, 13C NMR, FT-IR ve HRMS analizleri ile karakterize edildi. Moleküler doking çalışmalarının sonuçlarına göre en aktif molekülün, -10.098 kcal/mol docking skoru ve -64.97 kcal/mol serbest bağlanma enerjisine sahip bileşik Bold olduğu belirlendi. Bileşik 6-HER2 ligand-protein kompleksinin moleküler dinamik simülasyonunda simülasyon zamanının %70’i boyunca hidrojen bağı ve pi-pi staking etkileşimlerinin devam ettiği ve ligand atomlarının RMSD değerlerinin ortalamasının 2Å olduğu tespit edildi. Hedef bileşiklerin in siliko ADME parametrelerinin referans aralıklarda olduğu ve tahmini ADME sonuçlarına göre ilaç benzerliği taşıdığı görüldü. Ayrıca sonuçlar referans antikanser ilaç doksorubisinin ile karşılaştırıldı ve bazı parametrelerin doksorubisine göre daha anlamlı ve uygun olduğu tespit edildi. Sonuç olarak ilk defa bu çalışmada sentezlen bileşik Bold, meme kanserinin büyüme faktörü reseptörü olan HER2’ye karşı yapılan in siliko çalışmalara göre en iyi inhibitör adayı olabileceği belirlendi.

Anahtar Kelimeler

• Nipagin
• Hidrazon
• Moleküler Doking
• Moleküler Dinamik
• ADME

Synthesis of New Hydrazone Derivatives of Nipagin and Determination of their in Silico Biological Activities

Öz

In this study, eight compounds (4-11) with the arylidenehydrazide structure were synthesized in order to develop new selective and low-toxicity potential anti-cancer agents based on nipagin (methyl paraben, methyl-4-hydroxybenzoate) and these compounds were synthesized and the anti-cancer potential of these compounds against HER2, the breast cancer growth factor receptor, were investigated for the first time by in silico methods. For the first time, their efficacy against the disease was investigated by in silico methods. First of all, the binding scores and free binding energies of the target compounds on the related protein were determined by molecular docking studies, then the stability of protein-ligand complexes were determined by molecular dynamics studies and finally the predicted ADME parameters were calculated. Target compounds were characterized by 1H NMR, 13C NMR, FT-IR and HRMS analyses. Based on the molecular docking studies, the target molecule with the highest inhibition potential was determined as compound Bold with a docking score of -10.098 kcal/mol and a free binding energy of -64.97 kcal/mol. In the molecular dynamics simulation of the compound 6-HER2 ligand-protein complex, it was determined that hydrogen bonding and pi-pi stacking interactions continued for 70% of the simulation time and the average RMSD values of the ligand atoms were 2Å. It was observed that in silico ADME parameters of the target compounds were within reference ranges and had drug similarity according to the estimated ADME results. In addition, the results were compared with anticancer drug doxorubicin and some parameters were found to be more significant and appropriate than doxorubicin. As a result, compound Bold, which was synthesized for the first time in this study, was determined as the best inhibitor candidate according to in silico studies against HER2, the growth factor receptor of breast cancer.

Anahtar Kelimeler

• Nipagin
• Hyrazone
• Molecular Docking
• Molecular Dynamics
• ADME

Kaynakça

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