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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

Be Aware of Aggregators in the Search for Potential Human ecto-5 `-Nucleotidase Inhibitors

Texto completo
Autor(es):
Viviani, Lucas G. [1] ; Piccirillo, Erika [2, 1] ; Cheffer, Arquimedes [2] ; de Rezende, Leandro [2, 1] ; Ulrich, Henning [2] ; Carmona-Ribeiro, Ana Maria [2] ; T-do Amaral, Antonia [1]
Número total de Autores: 7
Afiliação do(s) autor(es):
[1] Univ Sao Paulo, Inst Quim, Dept Quim Fundamental, Av Prof Lineu Prestes 748, BR-05508000 Sao Paulo - Brazil
[2] Univ Sao Paulo, Inst Quim, Dept Bioquim, Av Prof Lineu Prestes 748, BR-05508000 Sao Paulo - Brazil
Número total de Afiliações: 2
Tipo de documento: Artigo Científico
Fonte: Molecules; v. 23, n. 8 AUG 2018.
Citações Web of Science: 1
Resumo

Promiscuous inhibition due to aggregate formation has been recognized as a major concern in drug discovery campaigns. Here, we report some aggregators identified in a virtual screening (VS) protocol to search for inhibitors of human ecto-5'-nucleotidase (ecto-5'-NT/CD73), a promising target for several diseases and pathophysiological events, including cancer, inflammation and autoimmune diseases. Four compounds ((A) under bar, (B) under bar, (C) under bar and (D) under bar), selected from the ZINC-11 database, showed IC50 values in the micromolar range, being at the same time computationally predicted as potential aggregators. To confirm if they inhibit human ecto-5'-NT via promiscuous mechanism, forming aggregates, enzymatic assays were done in the presence of 0.01% (v/v) Triton X-100 and an increase in the enzyme concentration by 10-fold. Under both experimental conditions, these four compounds showed a significant decrease in their inhibitory activities. To corroborate these findings, turbidimetric assays were performed, confirming that they form aggregate species. Additionally, aggregation kinetic studies were done by dynamic light scattering (DLS) for compound (C) under bar. None of the identified aggregators has been previously reported in the literature. For the first time, aggregation and promiscuous inhibition issues were systematically studied and evaluated for compounds selected by VS as potential inhibitors for human ecto-5'-NT. Together, our results reinforce the importance of accounting for potential false-positive hits acting by aggregation in drug discovery campaigns to avoid misleading assay results. (AU)

Processo FAPESP: 13/07937-8 - Redoxoma
Beneficiário:Ohara Augusto
Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
Processo FAPESP: 12/50880-4 - Células-tronco: dos papéis de receptores de cininas e purinas às aplicações terapêuticas
Beneficiário:Alexander Henning Ulrich
Linha de fomento: Auxílio à Pesquisa - Temático
Processo FAPESP: 14/07248-0 - Busca virtual de inibidores da ecto-5'-nucleotidase humana e da tiorredoxina redutase de Mycobacterium tuberculosis: proposição de modelos e validação experimental
Beneficiário:Lucas Gasparello Viviani
Linha de fomento: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 12/06633-2 - Busca racional de inibidores de proteases virais da Dengue e da Febre Aftosa
Beneficiário:Erika Piccirillo
Linha de fomento: Bolsas no Brasil - Doutorado Direto
Processo FAPESP: 16/12392-9 - 21st European symposium on Quantitative Structure-Activity Relationship where molecular simulations meet drug discovery
Beneficiário:Antonia Tavares Do Amaral
Linha de fomento: Auxílio à Pesquisa - Reunião - Exterior