Repurposing strategies on pyridazinone-based series by pharmacophore- and structure-driven screening.
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.
['Floresta|Giuseppe|G|', 'Crocetti|Letizia|L|http://orcid.org/0000-0003-3473-2683', 'Giovannoni|Maria Paola|MP|http://orcid.org/0000-0003-0310-7850', 'Biagini|Pierfrancesco|P|', 'Cilibrizzi|Agostino|A|http://orcid.org/0000-0002-9711-5183']
D001219:Aspartate Aminotransferases D002626:Chemistry, Pharmaceutical D004353:Drug Evaluation, Preclinical D004791:Enzyme Inhibitors D008024:Ligands D008958:Models, Molecular D015394:Molecular Structure D011724:Pyridazines D054852:Small Molecule Libraries
aspartate aminotransferase Pyridazinones drug repurposing pharmacophore model structure-based screening