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.

中文翻译：

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通过药效团和结构驱动的筛选重新利用基于哒嗪酮的系列策略。


我们在此报告通过反向虚拟筛选 (iVS) 方法对 52 种新型哒嗪酮小分子进行的计算机再利用研究。这些类似物最初被设计为甲酰肽受体（FPR）配体。正如药物发现项目中有时会出现的情况一样，随后的生物筛选证明这些分子在结合 FPR 方面无效，无法识别新的命中。通过集中的药物再利用方法，我们定义了多种适合与基于哒嗪酮的类似物库相互作用的潜在靶点。计算分析采用了两步法。具体来说，这些分子最初是通过基于药效团的筛选进行处理的。其次，通过对接研究和分子动力学模拟研究了所产生的结合特征，以明确确认“基于哒嗪酮的配体-靶蛋白”相互作用。我们的研究结果表明天冬氨酸转氨酶是该小分子系列最有利的重新利用靶标，值得在该领域进行额外的药物化学研究。