Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS Pilani), Pilani campus, Pilani 333 031, Rajasthan, India.
Laboratory of Natural Product Chemistry, Department of Pharmacy, Birla Institute of Technology and Science, Pilani (BITS Pilani), Pilani campus, Pilani 333 031, Rajasthan, India.
Bioorg Chem. 2019 Apr;85:373-381. doi: 10.1016/j.bioorg.2019.01.012. Epub 2019 Jan 8.
A series of eighteen indole glyoxylamide analogues were synthesized, characterized and evaluated for their pancreatic lipase inhibitory activity. Porcine pancreatic lipase (Type II) was used with 4-nitrophenyl butyrate (as substrate) for the in vitro assay. Compound 8f exhibited competitive inhibition against pancreatic lipase with IC value of 4.92 µM, comparable to that of the standard drug, orlistat (IC = 0.99 µM). Compounds 7a-i and 8a-i were subjected to molecular docking into the active site of human PL (PDB ID: 1LPB) wherein compound 8f possessed a potential MolDock score of -153.037 kcal/mol. Molecular dynamics simulation of 8f complexed with pancreatic lipase, confirmed the role of aromatic substitution in stabilizing the ligand through hydrophobic interactions (maximum observed RMSD = 3.5 Å).
合成了一系列十八个吲哚乙二酰亚胺类似物，并对其胰脂肪酶抑制活性进行了表征和评价。采用猪胰脂肪酶（II 型）和 4-硝基苯丁酸（作为底物）进行体外测定。化合物 8f 对胰脂肪酶表现出竞争性抑制作用，IC 值为 4.92 µM，与标准药物奥利司他（IC = 0.99 µM）相当。将化合物 7a-i 和 8a-i 进行分子对接，进入人 PL 的活性部位（PDB ID：1LPB），其中化合物 8f 具有潜在的 MolDock 评分-153.037 kcal/mol。与胰脂肪酶复合的 8f 的分子动力学模拟证实了芳基取代通过疏水相互作用稳定配体的作用（最大观察到的 RMSD = 3.5 Å）。
