SAR Analysis and Molecular Modeling Study of Some Pyridazine Derivatives for Discovery of New CDK2 Inhibitors

Öz

Pyridazines, which are rarely found in nature and are among the building blocks of macromolecules that are essential for the life of most living things, are a family of heterocyclic compounds with many different biological activities. In this study, it was aimed to examine the potential of 8 different pyridazine derivative compounds synthesized by Ünal et al. to be cyclin-dependent kinase 2 (CDK2) inhibitors, which take role in important cellular processes such as DNA replication so that the abnormalities observed in their activities are determined to be associated with cancer pathology. For this purpose, the conformer searchs of the compounds were performed using the semi-experimental PM6 method on the SPARTAN'14 program, the geometry optimizations and Structure-Activity Relations (SAR) analyzes were performed using the HF/6-31G(d) method. Furthermore, molecular docking studies of each compound for the selected active sites for the purpose of the study was carried out using Autodock Tools-1.5.6 and Autodock Vina programs. As a result of the study; it was determined that 1a2b (-10.8 kcal.mol-1) and 1b2b (-10.5 kcal.mol-1) compounds, which have the best affinity values among the compounds examined, have a high potential to be CDK2 inhibitors and it was become clear that advanced studies should be carried out considering the prominent features of these compounds for the design of new anticancer ligands.

Anahtar Kelimeler

• Pyridazine
• Molecular docking
• CDK2
• Anticancer
• Pyridazine, Molecular docking, CDK2, Anticancer

Yeni CDK2 İnhibitörlerinin Keşfedilmesi İçin Bazı Piridazin Türevi Bileşiklerin SAR Analizi ve Kenetlenme Çalışması

Öz

Doğada nadir olarak bulunan ve çoğu canlının yaşamı için elzem olan makro moleküllerin yapı taşları arasında yer alan piridazinler pek çok farklı biyolojik aktiviteye sahip olan bir heterosiklik bileşik ailesidir. Bu çalışmada Ünal ve grubu tarafından sentezlenen yeni 8 farklı piridazin türevi bileşiğin DNA replikasyonu gibi önemli hücresel süreçlerde rol alan ve bu nedenle aktivitesinde gözlenen anormalliklerin kanser patolojisi ile ilişkili olduğu belirlenen siklin bağımlı kinaz 2 (CDK2) inhibitörü olabilme potansiyellerinin incelenmesi amaçlanmıştır. Bu amaç doğrultusunda bileşiklerin konformer taramaları SPARTAN’14 programı üzerinde yarı deneysel PM6 yöntemi ile, geometri optimizasyonları ve Yapı-Aktivite İlişkileri (SAR) analizleri ise HF/6-31G(d) yöntemi kullanılarak gerçekleştirilmiştir. Her bir bileşiğin çalışmanın amacı doğrultusunda seçilen aktif bölgelere moleküler kenetlenme işlemleri ise Autodock Tools-1.5.6 ve Autodock Vina programları kullanılarak gerçekleştirilmiştir. Bu çalışma sonucunda; incelenen bileşikler arasından en iyi afinite değerlerine sahip olan 1a2b (-10,8 kkal.mol-1) ve 1b2b (-10,5 kkal.mol-1) bileşiklerinin CDK2 inhibitörü olabilme potansiyellerinin yüksek olduğu belirlenmiş ve yeni antikanser ajanı ligandların tasarımında bu bileşiklerin öne çıkan özelliklerinin dikkate alınmasıyla birlikte ilgili ileri düzey çalışmaların yapılması gerektiği açığa çıkmıştır.

Anahtar Kelimeler

• Piridazin
• Moleküler kenetlenme
• CDK2
• Antikanser

Kaynakça

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