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

Authors : Ebru Demet AKDOĞAN, Burak ERMAN, Kemal YELEKÇİ

Pages : 523-542

Doi:10.3906/sag-1211-54

View : 16 | Download : 8

Publication Date : 0000-00-00

Article Type : Research Paper

Abstract :Histone lysine-specific demethylase insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(polar surface area); versus ADMETAlogP98 insert ignore into journalissuearticles values(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 insert ignore into journalissuearticles values(tranylcypromine); and 2-insert ignore into journalissuearticles values(4-methoxy-phenyl); cyclopropylamine, which are the 2 known inhibitors of LSD1.
Keywords : LSD1, monamine oxidase, de novo design, selective inhibitors