AN IN SILICO PHARMACOKINETIC INVESTIGATION OF ORGANIC LUMINOGENS: UNDERSTANDING THE NIR AIEGENS AND THEIR INTERACTIONS WITH SERUM ALBUMINS

Yıl 2024, Cilt: 48 Sayı: 1, 56 - 74, 20.01.2024

Harun Nalçakan , Gülbin Kurtay , Dilara Tuğçe Özdil , Züleyha Yılmaz

https://doi.org/10.33483/jfpau.1335047

Öz

Objective: Fluorescence imaging (FLI) is accepted as a highly effective method for visualizing bioanalytics directly and gaining insight into complicated biological structures and processes. In this context, newly tailored organic molecules, which have the potential to be used in FLI, especially near-infrared (NIR) regions supported by aggregation-induced emission luminogens (AIEgens), are a rapidly developing area of study. Herein, using ADMET and molecular docking analyses, we examined the pharmacokinetic properties of both model (D2-A2-D2) and newly designed (Dn-An-Dn) organic luminogens to interact with blood proteins, namely bovine serum albumin (BSA) and human serum albumin (HSA), which have emerged as a versatile carrier of several therapeutic agents against preliminary cancer and infectious diseases.
Material and Method: The structural properties of the examined luminogens were computed using the Gaussian 09 software package. The DFT/B3LYP/6-31G(d,p) level was then utilized for geometry optimization and accurately determining electronic structures and molecular properties. Lipinski's rule of five was applied to predict the drugability of the compounds using the SwissADME web tool. Molinspiration was used for further validation of these properties and additional bioactivity parameters. Toxicity parameters were evaluated with OSIRIS Property Explorer (v.4.5.1). Molecular docking simulations of the luminogen-albumin complexes were performed using SAMSON 2022 R2 modeling platform and implemented Autodock-vina extension. The X-ray crystal structures of bovine serum albumin (BSA, PDB ID: 4F5S) and human serum albumin (HSA, PDB ID: 4L9Q) were obtained from the Protein Data Bank. Visualization of the docking interactions was conducted using Discovery Studio Visualizer 2021.
Result and Discussion: The compounds D1-A1-D1 and D1-A4-D1 stood out concerning molecular weight (MW) and ClogPo/w values, making them promising candidates for drug design. An analysis of lipophilicity revealed that these two compounds displayed high miLogP values, indicating a high degree of lipophilicity, which is generally beneficial for drug delivery. They also exhibited moderate bioactivity based on GPCR ligand and protease inhibitor (PI) parameters. On the other hand, D4-A3-D4 showcased paramount interaction with bovine serum albumin (BSA), while D5-A3-D5 demonstrated the highest binding affinity with human serum albumin (HSA).

Anahtar Kelimeler

ADMET, AIEgen, BSA, HSA, molecular docking

ORGANİK LUMİNOJENLERİN İN SİLİKO FARMAKOKİNETİK İNCELENMESİ: NIR AIEJENLERİ VE SERUM ALBÜMİNLERİ İLE ETKİLEŞİMLERİNİ ANLAMAK

Öz

Amaç: Floresans görüntüleme (FLI), biyoanalitikleri doğrudan görselleştirme ve karmaşık biyolojik yapıları ve süreçleri anlamak için son derece etkili bir yöntem olarak kabul edilir. Bu bağlamda, özellikle agregasyon-indüklü emisyon luminojenleri (AIEjen) tarafından desteklenen ve yakın kızılötesi (NIR) bölgede kullanılma potansiyeli olan yeni özelleştirilmiş organik moleküller, hızla gelişen bir çalışma alanıdır. Bu noktada, ADMET ve moleküler kenetlenme analizlerini kullanarak, hem model (D2-A2-D2) hem de yeni tasarlanmış (Dn-An-Dn) organik luminogenlerin kan proteinleri ile etkileşme özelliklerini farmakokinetik açıdan inceledik. Bu kan proteinleri, özellikle sığır serum albumini (BSA) ve insan serum albumini (HSA), erken kanser ve bulaşıcı hastalıklarla mücadelede çeşitli terapötik ajanların taşıyıcısı olarak öne çıkmıştır.
Gereç ve Yöntem: İncelenen luminojenlerin yapısal özellikleri Gaussian 09 yazılım paketi kullanılarak hesaplandı. Daha sonra DFT/B3LYP/6-31G(d,p) seviyesi, geometri optimizasyonu ve elektronik yapıların ve moleküler özelliklerin doğru bir şekilde belirlenmesi için kullanıldı. Bileşiklerin ilaçlaştırılabilirliğini tahmin etmek için Lipinski'nin beşli kuralı SwissADME web aracı kullanılarak uygulandı. Bu özelliklerin ve ek biyoaktivite parametrelerinin daha fazla doğrulanması için Molinspiration kullanıldı. Toksisite parametreleri OSIRIS Property Explorer (v.4.5.1) ile değerlendirildi. Luminojen-albümin komplekslerinin moleküler kenetlenme simülasyonları SAMSON 2022 R2 modelleme platformu ve Autodock-vina uzantısı kullanılarak gerçekleştirildi. Sığır serum albümininin (BSA, PDB ID: 4F5S) ve insan serum albümininin (HSA, PDB ID: 4L9Q) X-ışını kristal yapıları Protein Data Bank'tan alındı. Bağlanma etkileşimlerinin görselleştirilmesi Discovery Studio Visualizer 2021 kullanılarak gerçekleştirildi.
Sonuç ve Tartışma: D1-A1-D1 ve D1-A4-D1 bileşikleri, moleküler ağırlık (MA) ve ClogPo/w değerleri açısından öne çıkarak onları ilaç tasarımı için umut verici adaylar haline getirdi. Lipofilisite analizi, bu iki bileşiğin yüksek miLogP değerleri gösterdiğini ortaya çıkardı ki bu genellikle ilaç taşınım için istenen yüksek derecede lipofilikliğe işaret etmektedir. Ayrıca bu bileşikler, GPCR ligandı ve proteaz inhibitörü (PI) parametrelerine dayalı olarak da orta düzeyde biyoaktivite sergilediler. Öte yandan D4-A3-D4, sığır serum albümini (BSA) ile olağanüstü etkileşim sergilerken, D5-A3-D5, insan serum albümini (HSA) ile en yüksek bağlanma afinitesini gösterdi.

Anahtar Kelimeler

ADMET, AIEjen, BSA, HSA, moleküler kenetlenme

Kaynakça

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