Discovery of novel chromone and acrylate-based pancreatic lipase inhibitors: Molecular modelling, synthesis, and in vitro evaluation for the treatment of obesity,Chemical Biology & Drug Design

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Discovery of novel chromone and acrylate-based pancreatic lipase inhibitors: Molecular modelling, synthesis, and in vitro evaluation for the treatment of obesity
Chemical Biology & Drug Design ( IF 3.2 ) Pub Date : 2024-01-23 , DOI: 10.1111/cbdd.14443
Prashant S. Auti ₁ , Atish T. Paul ₁

Affiliation

By the optimization of previously established pancreatic lipase (PL) inhibitory lead, we have developed novel chromone-containing analogues with embedded acrylate fragment as potential PL inhibitors. The analogues were designed by considering the structural features required for binding at the active site of PL enzyme with the utilization of molecular docking study. An optimized synthetic scheme was utilized for the synthesis of designed analogues of prototypes 1&2. Through in vitro PL inhibitory screening, three analogues namely, 5fj, 5gj and 9a were identified as potent PL inhibitory leads with IC₅₀ values of 4.92, 4.23 and 3.32 μM, respectively. The protein binding of analogue 9a was analysed by fluorescence quenching study and it was found to bind at one binding site with a binding constant of 1.93 × 10⁵ L mol⁻¹. Analogue 9a also exhibited a competitive inhibitory mechanism with K_i value of 1.601 μM. In future, the potent lead 9a can be optimized to get a comparable or more potential PL inhibitory activity than marketed drugs.

中文翻译：

新型色酮和丙烯酸酯类胰腺脂肪酶抑制剂的发现：治疗肥胖的分子建模、合成和体外评估

通过优化先前建立的胰脂肪酶 (PL) 抑制先导化合物，我们开发了新型含色酮类似物，其中嵌入丙烯酸酯片段作为潜在的 PL 抑制剂。利用分子对接研究，考虑了与PL酶活性位点结合所需的结构特征，设计了类似物。采用优化的合成方案来合成原型 1 和 2 的设计类似物。通过体外PL抑制筛选，三种类似物5fj、5gj和9a被鉴定为有效的PL抑制先导化合物，IC ₅₀值分别为4.92、4.23和3.32 μM。通过荧光猝灭研究分析了类似物9a的蛋白结合情况，发现其在一个结合位点结合，结合常数为1.93×10 5 ^L mol ^-1。类似物9a也表现出竞争性抑制机制，K _i值为1.601 μM。未来，可以对强效先导物9a进行优化，以获得与市售药物相当或更具潜力的 PL 抑制活性。

更新日期：2024-01-25

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