Ellagik Asit’in De Novo İlaç Analogları Kullanılarak in Silico Biyokimya ile VEGFR1 Reseptörü Aracılığıyla Karaciğer Kanserinin İnhibisyonu: Kapsamlı ADMET, RMSD, Moleküler Kenetlenme ve Molecular Dinamik Simülasyonları

Öz

Amaç: İyi bilinen farmakognostik moleküllerden biri olan Ellagik Asidin, VEGFR1 reseptör mekaniz-ması üzerinden karaciğer kanserini baskılamak hedefli ilaç adayı olarak kullanılmak üzere, yeni tasarala-nan türevlerinde büyük bir potansiyele sahip olduğu keşfedilmiştir. Bu çalışma, karaciğer kanseri anjiyo-genezinde rol oynayan VEGFR1 reseptörüne karşı inhibitör bağlanmayı iyileştirmek amacıyla, Ellagik Asidin iki yeni türevi olan hidroksillenmiş bir analog ve bir Ellagik Asit-Kuersetin birlikte ilacının tasa-rımını in silico biyokimya simülasyonu yoluyla gerçekleştirmeyi amaçlamıştır. Yöntemler: Üç boyutlu ligand yapıları, B3LYP/6-31G(d,p) temel seti kullanılarak yoğunluk fonksiyonel teorisi (DFT) ile oluşturulup optimize edilmiştir. Moleküler kenetlenme simülasyonları AutoDock Vina 1.2.0 ile gerçekleştirilmiştir. En uygun bağlanma pozisyonları, Desmond Maestro 2024-2 yazılımı ile NPT koşullarında (310 K, 1,01 bar) OPLS 3.0 kuvvet alanı altında moleküler dinamik (MD) simülas-yonlarına tabi tutulmuştur. Bağlanma serbest enerjileri MM/GBSA hesaplamaları ile değerlendirilmiştir. Bulgular: Saf Ellagik Asit, moleküler dinamik analizlerinde -89,236 kJ/mol bağlanma enerjisine sahip-ken; hidroksillenmiş yeni analogu -105,319 kJ/mol ve Ellagik Asit-Kuersetin birlikte ilacı -147,214 kJ/mol bağlanma enerjisi göstermiştir. İki yeni ilacın inhibisyon sabiti değerleri, saf Ellagik Asit’e kıyasla dokuz kat daha yüksek inhibitör etkiye sahiptir; bu durum, VEGFR1 reseptörünün aktif bölgesine daha düşük dozlarda dahi etkin bağlanabildiklerini kanıtlamaktadır. Sonuçlar: Ellagik Asidin iki analogunda elde edilen sonuçlar saf Ellagic Aside kıyasla o kadar iyidir ki, VEGFR1 karaciğer kanseri transmembran reseptör inhibitörü olarak kullanılmaları açısından önemlerini in silico simulasyonel çalışmalar açısından kanıtlamışlardır. Bu nedenle, bu yeni moleküller, ileride çalışı-lacak olan in vitro hücre hattı toksisitesi ve in vivo çalışmaları için geleceğe ışık tutmaktadır.

Anahtar Kelimeler

• In Silico İlaç Keşfi
• Ellagik Asit
• VEGFR1
• Moleküler Kenetlenme
• Moleküler Dinamikler
• RMSD
• MM/GBSA
• ADMET

INHIBITING LIVER CANCER VIA THE VEGFR1 RECEPTOR PROTEIN USING IN SILICO BIOCHEMISTRY DE NOVO DRUG ANALOGUES OF ELLAGIC ACID: COMPREHENSIVE ADMET, RMSD, MOLECULAR DOCKING, AND MOLECULAR DYNAMICS SIMULATIONS

Öz

Objective: Ellagic Acid, one of the well-known Pharmacognostic molecules, has been discovered to have great potential in its new derivatives to be used as drug candidates to suppress liver cancer via the VEGFR1 receptor mechanism. This study aimed to simulate (in silico biochemistry) design two novel derivatives of Ellagic Acid, a hydroxylated analogue and an Ellagic Acid–Quercetin co-drug, to improve inhibitory binding against the VEGFR1 receptor implicated in liver cancer angiogenesis. Methods: Three-dimensional ligand structures were built and optimized using density functional theory (DFT) with the B3LYP/6-31G(d,p) basis set. Molecular docking simulations were performed using AutoDock Vina 1.2.0. The most favorable poses were subjected to molecular dynamics (MD) simulations in Desmond Maestro 2024-2 under NPT conditions (310 K, 1.01 bar) with the OPLS 3.0 force field. Binding free energies were assessed using MM/GBSA calculations. Results: The pristine Ellagic Acid possesses -89.236 kJ/mol of binding energy in Molecular Dynamics, where its de novo Hydroxylated analogue and Ellagic Acid-Quercetin co-drug possess -105.319 kJ/mol, -147.214 kJ/mol, respectively. The inhibition constant values of the two new drugs are nine times higher compared to pristine Ellagic Acid, proving their efficacy with much less dosage usage in the binding of VEGFR1 receptor’s active site. Conclusion: In two analogues of Ellagic Acid, results are so much better that they prove their worth from the perspective of in silico simulation studies in terms of being used as a VEGFR1 liver cancer transmembrane receptor inhibitor. Thus, these new molecules shed light on further in vitro cell line toxicity and in vivo studies for the future.

Anahtar Kelimeler

• In Silico Drug Discovery
• Ellagic Acid
• Molecular Docking
• Molecular Dynamics
• RMSD
• MM/GBSA
• ADMET

Kaynakça

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