In silico design of novel and highly selective lysine-specific histone demethylase inhibitors

Ebru Demet AKDOĞAN; Burak ERMAN; Kemal YELEKÇİ

Makale detayları

In silico design of novel and highly selective lysine-specific histone demethylase inhibitors

Yazarlar:

Ebru Demet AKDOĞAN | Burak ERMAN | Kemal YELEKÇİ

Yayıncı:

TUBITAK

Dergi:

Turkish Journal of Chemistry 2011 Vol.35 Issue 4, pp.523-542

Belge Tipi:

Makale

Yayın Tarihi:

3/2011

Belge Dili:

Türkçe

Document ID (Org No.):

2000727782

Sıklık:

İki Aylık

eISSN:

1303-6130

pISSN:

1300-0527

Özet:

 

Histone lysine-specific demethylase (LSD1) is involved in a  wide range of epigenetic processes and plays important roles in gene  silencing, DNA transcription, DNA replication, DNA repair, and  heterochromatin formation.  Its active site shows a resemblance to  those of 2 homologous enzymes, monamine oxidase A and B (MAO-A and  MAO-B.) In the present work, starting from suitable scaffolds and  generating thousands of structures from them, 10 potential inhibitors  were obtained with structural and physicochemical properties  selectively suitable for inhibiting LSD1.  iLib Diverse software was  used to generate the diverse structures and 3 docking tools, CDOCKER,  GOLD, and AutoDock, were used to find the most probable potential  inhibitor based on its binding affinity.  The dispositions of the  candidate molecules within the organism were checked by ADMETPSA2D  (polar surface area) versus ADMETAlogP98 (the logarithm of the  partition coefficient between n-octanol and water), and their  suitability is discussed.  The LSD1 inhibition activities of the  candidates were compared with the properties of  trans-2-phenylcyclopropylamine (tranylcypromine) and  2-(4-methoxy-phenyl) cyclopropylamine, which are the 2 known  inhibitors of LSD1.

 

Histone lysine-specific demethylase (LSD1) is involved in a  wide range of epigenetic processes and plays important roles in gene  silencing, DNA transcription, DNA replication, DNA repair, and  heterochromatin formation.  Its active site shows a resemblance to  those of 2 homologous enzymes, monamine oxidase A and B (MAO-A and  MAO-B.) In the present work, starting from suitable scaffolds and  generating thousands of structures from them, 10 potential inhibitors  were obtained with structural and physicochemical properties  selectively suitable for inhibiting LSD1.  iLib Diverse software was  used to generate the diverse structures and 3 docking tools, CDOCKER,  GOLD, and AutoDock, were used to find the most probable potential  inhibitor based on its binding affinity.  The dispositions of the  candidate molecules within the organism were checked by ADMETPSA2D  (polar surface area) versus ADMETAlogP98 (the logarithm of the  partition coefficient between n-octanol and water), and their  suitability is discussed.  The LSD1 inhibition activities of the  candidates were compared with the properties of  trans-2-phenylcyclopropylamine (tranylcypromine) and  2-(4-methoxy-phenyl) cyclopropylamine, which are the 2 known  inhibitors of LSD1.

Makale detayları

In silico design of novel and highly selective lysine-specific histone demethylase inhibitors

Yazarlar: Ebru Demet AKDOĞAN | Burak ERMAN | Kemal YELEKÇİ

Yayıncı: TUBITAK

Dergi: Turkish Journal of Chemistry 2011 Vol.35 Issue 4, pp.523-542

Belge Tipi: Makale

Yayın Tarihi: 3/2011

Belge Dili: Türkçe

Document ID (Org No.): 2000727782

Sıklık: İki Aylık

eISSN: 1303-6130

pISSN: 1300-0527

Sayı

Yazarlar:

Ebru Demet AKDOĞAN | Burak ERMAN | Kemal YELEKÇİ

Yayıncı:

TUBITAK

Dergi:

Turkish Journal of Chemistry 2011 Vol.35 Issue 4, pp.523-542

Belge Tipi:

Makale

Yayın Tarihi:

3/2011

Belge Dili:

Türkçe

Document ID (Org No.):

2000727782

Sıklık:

İki Aylık

eISSN:

1303-6130

pISSN:

1300-0527