Repurposing strategies on pyridazinone-based series by pharmacophore- and structure-driven screening

Autor: Giuseppe Floresta, Letizia Crocetti, Maria Paola Giovannoni, Pierfrancesco Biagini, Agostino Cilibrizzi
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 35, Iss 1, Pp 1137-1144 (2020)
Druh dokumentu: article
ISSN: 1475-6366
1475-6374
14756366
DOI: 10.1080/14756366.2020.1760261
Popis: We report here in silico repurposing studies on 52 new pyridazinone-based small-molecules through inverse virtual screening (iVS) methodologies. These analogues were originally designed as formyl peptide receptor (FPR) ligands. As it is sometimes the case in drug discovery programmes, subsequent biological screening demonstrated the inefficacy of the molecules in binding FPRs, failing in the identification of new hits. Through a focussed drug-repurposing approach we have defined a variety of potential targets that are suitable to interact with this library of pyridazinone-based analogues. A two-step approach has been conducted for computational analysis. Specifically, the molecules were initially processed through a pharmacophore-based screening. Secondly, the resulting features of binding were investigated by docking studies and following molecular dynamic simulations, in order to univocally confirm “pyridazinone-based ligand-target protein” interactions. Our findings propose aspartate aminotransferase as the most favourable repurposed target for this small-molecule series, worth of additional medicinal chemistry investigations in the field.
Databáze: Directory of Open Access Journals
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