Molecular Docking Mediated Virtual Drug Screening for GABAA Receptor: Promising Digoxin Derivatives

Year 2023, Volume: 51 Issue: 1, 71 - 91, 01.01.2023

Hüseyin Saygın Portakal

https://doi.org/10.15671/hjbc.1139995

Abstract

In the central nervous system (CNS) of mammalian species, ℽ-aminobutyric acid (GABA) is the primary inhibitory neurotransmitter due to it regulates neuronal development through leading neural differentiation, proliferation, migration, etc. GABAA receptor is the major GABA receptor since it has the highest expression level among the other GABA receptors within CNS. Many pieces of evidence prove that the defects in the GABAergic pathway might give rise to serious diseases such as schizophrenia, epilepsy, anxiety, depression, insomnia, etc. In this study drug library with a totally of 8170 ligands consists of three distinct datasets which are FDA-approved Drugs, Drugs Approved by World but not FDA, and Non-human Metabolites have been screened for the allosteric site of the GABAA receptor with PyRx Virtual Screening Tool and ligand-receptor interactions have been analyzed with Biovia Discovery Studio software. Results reveal that Digoxin and its two distinct derivatives (DD1 and DD2), as well as Conivaptan, are promising in the treatment of GABAergic pathway-based disorders. The findings of this report should be verified with further molecular dynamics (MD) simulations and the ligands should be tested by both in vitro and in vivo studies.

Keywords

Virtual drug screening, Molecular docking, GABA, GABAergic pathway, Central nervous system, Nervous disorders

Moleküler Yanaştırma Yöntemiyle GABAA Reseptörü İçin Sanal İlaç Tarama: Umut Veren Digoksin Türevleri

Abstract

Memeli türlerinin merkezi sinir sisteminde (MSS) ℽ-aminobütirik asit (GABA), nöral farklılaşma, çoğalma, göç vb. yolakları düzenleyen nöronal gelişim için birincil inhibitör nörotransmiterdir. GABAA reseptörü MSS içindeki diğer GABA reseptörleri arasında en yüksek ekspresyon seviyesine sahip olduğu için majör GABA reseptörüdür. GABAerjik yolaktaki bozuklukların şizofreni, epilepsi, anksiyete, depresyon, uykusuzluk gibi ciddi hastalıklara yol açabileceğini gösteren pek çok kanıt bulunmaktadır. Bu çalışmada FDA Onaylı İlaçlar, Dünyaca Onaylı Ama FDA Onaylı Olmayan İlaçlar ve İnsan Dışı Metabolitler olarak üç farklı verisetinden oluşan toplam 8170 ligand içeren ilaç kütüphanesi GABAA reseptörünün allosterik bölgesi için PyRx Virtual Screening Tool ile taranmış ve ligand-reseptör etkileşimleri Biovia Discovery Studio yazılımı ile analiz edilmiştir. Sonuçlar, Digoksin ve iki farklı türevinin (DD1 ve DD2) ve ayrıca Conivaptan'ın GABAerjik yolak temelli bozuklukların tedavisinde umut verici olduğunu ortaya koymaktadır. Bu raporun bulguları daha ileri moleküler dinamik (MD) simülasyonları ile doğrulanmalı ve ligandlar hem in vitro hem de in vivo çalışmalarla test edilmelidir.

Keywords

Sanal ilaç tarama, Moleküler yanaştırma, GABA, GABAerjik yolak, Merkezi sinir sistemi, Sinir sistemi bozuklukları

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