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

Hüseyin Saygın Portakal

Makale detayları

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

Yazarlar:

Hüseyin Saygın Portakal

Yayıncı:

Hacettepe University

Ana Başlıklar:

Engineering

Dergi:

Hacettepe Journal of Biology and Chemistry Vol.51 Issue 1, pp.71-91

Belge Tipi:

Makale

Yayın Tarihi:

1/2023

Belge Dili:

İngilizce

Document ID (Org No.):

2001281387

pISSN:

2687-475X

Anahtar kelimeler:

Özet:

 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.

 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.

 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.

 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 Conivaptanın 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.

Makale detayları

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

Yazarlar:

Hüseyin Saygın Portakal

Yayıncı:

Hacettepe University

Ana Başlıklar:

Engineering

Dergi:

Hacettepe Journal of Biology and Chemistry Vol.51 Issue 1, pp.71-91

Belge Tipi:

Makale

Yayın Tarihi:

1/2023

Belge Dili:

İngilizce

Document ID (Org No.):

2001281387

pISSN:

2687-475X

Virtual drug screening

Molecular docking

GABA

GABAergic pathway

Central nervous system

Nervous disorders

Sanal ilaç tarama

Moleküler yanaştırma

GABA

GABAerjik yolak

Merkezi sinir sistemi

Sinir sistemi bozuklukları

Sayı

Makale detayları

Yazarlar: Hüseyin Saygın Portakal

Yayıncı: Hacettepe University

Ana Başlıklar: Engineering

Dergi: Hacettepe Journal of Biology and Chemistry Vol.51 Issue 1, pp.71-91

Belge Tipi: Makale

Yayın Tarihi: 1/2023

Belge Dili: İngilizce

Document ID (Org No.): 2001281387

pISSN: 2687-475X

Sayı

Yazarlar:

Hüseyin Saygın Portakal

Yayıncı:

Hacettepe University

Ana Başlıklar:

Engineering

Dergi:

Hacettepe Journal of Biology and Chemistry Vol.51 Issue 1, pp.71-91

Belge Tipi:

Makale

Yayın Tarihi:

1/2023

Belge Dili:

İngilizce

Document ID (Org No.):

2001281387

pISSN:

2687-475X