Virtual screening and Quantitative Structure-Activity Relationships of selective LSD1 inhibitors

• Grant number: 14/21883-0
• Support Opportunities: Scholarships in Brazil - Scientific Initiation
• Start date: March 01, 2015
• End date: February 28, 2017
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Gustavo Henrique Goulart Trossini
• Grantee: Giovani Luiz Genesi
• Host Institution: Faculdade de Ciências Farmacêuticas (FCF). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Histone modifications, such as methylation, acetylation and phosphorylation, play a pivotal role on epigenetic control of gene expression. Among such modifications, histone methylation is reversibly regulated by histone methyltransferases and demethylases. Lysine-Specific Demethylase 1 (LSD1), the first identified histone demethylase, is part of a large family of amino oxidases and catalyzes the FAD-dependent removal of methyl groups from lysines 4 and 9 of histone H3 (H3K4 and H3K9). Overexpression of LSD1 is observed in several types of cancer, with its activity being essential for maintaining cancer cells. Pharmacological inhibition of LSD1 activity has been shown to block cancer progression. Hence, LSD1 has been pointed out as a promising biological target for the development of new drugs with potential for anticancer therapy. Several LSD1 inhibitors have been reported - such as trans-2-phenylcyclopropylamine (tranylcypromine), a monoamino oxidase inhibitor approved for clinical use as antidepressant -, although none has been approved for clinical use so far. The main purpose of this project is to employ Virtual Screening techniques in the search for novel selective inhibitors of LSD1, as well as to perform quantitative structure-activity relationship (QSAR) studies in order to assist in the drug design of novel LSD1 inhibitors. (AU)