Hologram quantitative structure-activity relationship and comparative molecular interaction field analysis of aminothiazole and thiazolesulfonamide as reversible LSD1 inhibitors

Autor(es)

Maltarollo, Vinicius G. ^[1] ; Honorio, Kathia M. ^{[2, 3]} ; Emery, Flavio S. ^[4] ; Ganesan, Arasu ^[5] ; Trossini, Gustavo H. G. ^[1]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Fac Pharmaceut Sci, Sao Paulo - Brazil

^[2] Univ Sao Paulo, Sch Arts Sci & Humanities, Sao Paulo - Brazil

^[3] Fed Univ ABC, Ctr Nat & Human Sci, Sao Paulo - Brazil

^[4] Univ Sao Paulo, Fac Pharmaceut Sci Ribeirao Preto, QHETEM, Sao Paulo - Brazil

^[5] Univ E Anglia, Sch Pharm, Norwich NR4 7TJ, Norfolk - England

• Tipo de documento: Artigo Científico
• Fonte: Future Medicinal Chemistry; v. 7, n. 11, p. 1381-1394, 2015.
• Citações Web of Science: 3

Resumo

Background: LSD-1 is an enzyme that removes methyl groups from lysine residues of histone proteins. LSD-1 inhibition decreases cellular proliferation and therefore represents a therapeutic target for cancer treatment. MAO and LSD-1 are both flavin adenine dinucleotide-dependent MAOs, and the MAO inhibitor, tranylcypromine, is currently undergoing clinical trials for cancer treatment because it acts as an irreversible LSD-1 inhibitor. Materials \& methods: The present study investigated new reversible LSD-1 inhibitors, in order to develop novel selective anticancer agents. We constructed 2 and 3D quantitative structure-activity relationship models by using a series of 54 aminothiazole and thiazolesulfonamide derivatives. Results: The models were validated internally and externally (q(2), 0.691 and 0.701; r(2), 0.894 and 0.937; r(test)(2), 0.785 and 0.644, for 2 and 3D models, respectively). Fragment contribution maps, as well as steric and electrostatic contour maps were generated in order to obtain chemical information related to LSD-1 inhibition. Conclusion: The thiazolesulfonamide group was fundamental to the inhibition of LSD-1 by these compounds and that bulky and aromatic substituents at the thiazole ring were important for their steric and electrostatic interactions with the active site of LSD-1. (AU)

• Processo FAPESP: 12/20990-2 - Agentes anti-infecciosos: uma evolução dos estudos químico-medicinais de naftotiazóis leishmanicidas e a busca de novos agentes tuberculostáticos
• Beneficiário: Flavio da Silva Emery
• Modalidade de apoio: Auxílio à Pesquisa - Regular