Design, Molecular Docking and Molecular Dynamics Simulation Studies of Novel Pyridinecarboxamide Derivatives as Potent HDAC6 inhibitors

Yıl 2025, Cilt: 41 Sayı: 1, 165 - 174, 30.04.2025

İsmail Akçok

Öz

Histone deacetylases (HDACs) are a family of enzymes which play vital roles in the regulation of gene expression and cellular processes. HDACs are classified into four main classes based on their homology, cellular localization, and structural characteristics. HDAC6 enzyme which is one of the class IIb enzyme has important functions in variety of physiological processes such as cell migration, immune responses, and neuronal function. Dysregulation of HDAC6 activity has been linked to the accumulation of toxic protein aggregates in neurodegenerative diseases, while its overexpression or altered activity in cancer cells can contribute to metastasis and tumorigenesis. In this study, potential HDAC6 inhibitors were designed and their inhibitory activities were investigated using in silico protocols, including molecular docking, molecular dynamics simulations and MM-PBSA calculations. Among the designed molecules, IA64 showed the best binding profile against HDAC6 enzyme, and could be considered as a lead molecule for further studies.

Anahtar Kelimeler

Drug design, cancer, HDAC6, Molecular docking, MD simulations

Potansiyel HDAC6 İnhibitörleri Olarak Yeni Piridinkarboksamid Türevlerinin Tasarım, Moleküler Kenetlenme ve Moleküler Dinamik Simülasyon Çalışmaları

Öz

Histon deasetilazlar (HDACs), gen ifadesinin ve hücresel süreçlerin düzenlenmesinde önemli rol oynayan bir enzim ailesidir. HDAC enzimleri homolojilerine, hücresel lokalizasyonlarına ve yapısal özelliklerine göre dört ana sınıfa ayrılır. Sınıf IIb enzimlerinden biri olan HDAC6 enzimi, hücre göçü, bağışıklık tepkileri ve nöronal işlev gibi çeşitli fizyolojik süreçlerde önemli işlevlere sahiptir. HDAC6 aktivitesinin düzensizliği, nörodejeneratif hastalıklarda toksik protein agregatlarının birikimiyle ilişkilendirilmiştir; kanser hücrelerinde aşırı ifadesi veya değişen aktivitesi ise metastaz ve tümör oluşumuna sebep olabilmektedir. Bu çalışmada, potansiyel HDAC6 inhibitörleri tasarlanmış ve bu moleküllerin inhibisyon potansiyelleri, moleküler kenetlenme, moleküler dinamik simülasyonları ve MM-PBSA hesaplamalarını içeren in silico protokolleri kullanılarak araştırılmıştır. Tasarlanan moleküller arasında IA64, HDAC6 enzimine karşı en iyi bağlanma profilini göstermiştir ve ileri çalışmalar için öncü bir molekül olarak görülebilir.

Anahtar Kelimeler

ilaç tasarımı, kanser, HDAC6, Moleküler Kenetlenme, MD simulasyonu

Kaynakça

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