| Texto completo | |
| Autor(es): |
Viviani, Lucas G.
;
Piccirillo, Erika
;
Ulrich, Henning
;
Amaral, Antonia T-do
Número total de Autores: 4
|
| Tipo de documento: | Artigo Científico |
| Fonte: | JOURNAL OF CHEMICAL INFORMATION AND MODELING; v. 60, n. 2, p. 10-pg., 2020-02-01. |
| Resumo | |
Ecto-5'-nucleotidase (ecto-5'-NT, CD73) is a zinc-binding metallophosphatase that plays a key role in extracellular purinergic pathways, being implicated in several physiological and pathophysiological processes, such as immune homeostasis, inflammation, and tumor progression. As such, it has been recognized as a promising biological target for many diseases, including cancer, infections, and autoimmune diseases. Despite its importance, so far only a few inhibitors of this target enzyme are known, most of which are not suitable as drug candidates. Here, we aimed to search for hydroxamic acid-containing compounds as potential human ecto-5'-NT inhibitors, since this group is known to be a strong zinc chelator. To this end, we performed a hierarchical virtual screening (VS) search consisting of three consecutive steps (filtering for compounds bearing a hydroxamic acid group, shape-based matching, and docking followed by visual inspection), which were applied to screen the ZINC-14 database ("all purchasable subset"). Out of 25 compounds selected by this VS protocol, 12 were acquired and further submitted to enzymatic assays for VS experimental validation. Four of them (i.e., 33.3%) were found to inhibit human ecto-5'-NT in the low micromolar range. The most potent one showed an IC50 value of 6.2 +/- 1.0 mu M. All identified inhibitors satisfy drug-like criteria and provide novel scaffolds to be explored in further hit-to-lead optimization steps. Furthermore, to the best of our knowledge, they are the first hydroxamic acid-containing inhibitors of human ecto-5'-NT described so far. (AU) | |
| Processo FAPESP: | 13/07937-8 - Redoxoma |
| Beneficiário: | Ohara Augusto |
| Modalidade de apoio: | 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 |
| Modalidade de apoio: | Auxílio à Pesquisa - Temático |
| Processo FAPESP: | 18/06381-0 - Uso de simulações de dinâmica molecular (DM) para estudar a flexibilidade da ecto-5'-nucleotidase humana (ecto-5'NT, CD73) e TRAPP (Transient Pockets in Proteins) para análises da dinâmica de sítios de ligação |
| Beneficiário: | Lucas Gasparello Viviani |
| Modalidade de apoio: | Bolsas no Exterior - Estágio de Pesquisa - Doutorado Direto |
| Processo FAPESP: | 18/24678-0 - Busca virtual de novos inibidores da angiogênese patológica |
| Beneficiário: | Erika Piccirillo |
| Modalidade de apoio: | Bolsas no Brasil - Pós-Doutorado |
| Processo FAPESP: | 12/06633-2 - Busca racional de inibidores de proteases virais da Dengue e da Febre Aftosa |
| Beneficiário: | Erika Piccirillo |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado Direto |
| Processo FAPESP: | 18/07366-4 - Receptores de purinas e cininas como alvos de estudo e intervenção terapêutica em doenças neurológicas |
| Beneficiário: | Alexander Henning Ulrich |
| Modalidade de apoio: | 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 |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado Direto |