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


Abstract: 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 ADMET_PSA_2D (polar surface area) versus ADMET_AlogP98 (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.

Keywords: LSD1, monamine oxidase, de novo design, selective inhibitors

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