Yadav Nisha, Paul Atish T
Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS Pilani), Pilani, Rajasthan, India.
Chem Biol Drug Des. 2025 Jan;105(1):e70046. doi: 10.1111/cbdd.70046.
A set of coumarin-3-carboxamide analogues were designed, synthesized, and evaluated for their ability to impede pancreatic lipase (PL) activity. Out of all the analogues, 5dh and 5de demonstrated promising inhibitory activity against PL, as indicated by their respective IC values of 9.20 and 11.4 μM, as compared to Orlistat (IC = 0.97 μM). It was found that analogue 5dh inhibited PL in a competitive manner with an inhibition constant (K) of 4.504 μM. Additionally, the docking analysis validated the interactions between the analogue 5dh (MolDock score of -140.251 kcal/mol) and key amino acids in the active site, including Leu 153, Gly 76, Arg 256, His 151, Phe 77, and His 263. The inhibitory activity of these analogues was significantly correlated with their MolDock scores (Pearson's r = 0.6586). Finally, molecular dynamics simulation was also performed for 100 ns in order to elucidate the stability, confirmation and intermolecular interactions of the active analogue 5dh. The results of this investigation suggested that the complex maintained its stability despite the dynamic conditions exhibiting interactions with important amino acids. In summary, the outcomes indicated that the synthesized analogues exhibited the potential to inhibit PL activity.
设计、合成了一组香豆素 - 3 - 甲酰胺类似物，并评估了它们抑制胰腺脂肪酶（PL）活性的能力。在所有类似物中，5dh和5de对PL表现出有前景的抑制活性，其各自的IC值分别为9.20和11.4 μM，相比之下，奥利司他的IC值为0.97 μM。发现类似物5dh以竞争性方式抑制PL，抑制常数（K）为4.504 μM。此外，对接分析验证了类似物5dh（MolDock评分为 - 140.251 kcal/mol）与活性位点中的关键氨基酸之间的相互作用，包括Leu 153、Gly 76、Arg 256、His 151、Phe 77和His 263。这些类似物的抑制活性与它们的MolDock评分显著相关（皮尔逊r = 0.6586）。最后，还进行了100 ns的分子动力学模拟，以阐明活性类似物5dh的稳定性、构象和分子间相互作用。该研究结果表明，尽管处于动态条件下且与重要氨基酸存在相互作用，但该复合物仍保持其稳定性。总之，结果表明合成的类似物具有抑制PL活性的潜力。
