Amarogentin is mainly extracted from Swertia and Gentiana roots. It plays cemopreventive/therapeutic role during liver carcinogenesis through modulation of cell cycle and apoptosis

Amarogentin，一种来自S. chirayita的苦味secoiridoid glycoside，在多种病理生理条件下展现出不同的活性，主要在利什曼病和癌症生成中表现突出。实验分析揭示，Amarogentin通过下调cyclooxygenase-2 (COX-2)活性，有助于抑制小鼠模型中的皮肤癌生成；然而，对Amarogentin选择性抑制可诱导的cyclooxygenase (COX)亚型尚无报道[1]。Amarogentin抑制人类胃癌细胞SNU-16的生长（48小时后IC50 = 12.4μM），当浓度达到50μM时增加细胞凋亡。Amarogentin（10-50 mg/kg，s.c.）在SNU-16裸鼠异种移植模型中剂量依赖性地减少肿瘤生长[2]。

The computer-aided drug discovery methods were used to unravel the COX-2 inhibitory mechanism of Amarogentin and to check its selectivity for the inducible isoform over the constitutive one.?The generated theoretical models of both isoforms were subjected to molecular docking analysis with Amarogentin and twenty-one other Food and Drug Authority (FDA) approved lead molecules.?The post-docking binding energy profile of Amarogentin was comparable to the binding energy profiles of the FDA approved selective COX-2 inhibitors.?Subsequent molecular dynamics simulation analysis delineated the difference in the stability of both complexes, with Amarogentin-COX-2 complex being more stable after 40ns simulation.?The total binding free energy calculated by MMGBSA for the Amarogentin-COX-2 complex was -52.35 KCal/mol against a binding free energy of -8.57 KCal/mol for Amarogentin-COX-1 complex, suggesting a possible selective inhibition of the COX-2 protein by the natural inhibitor.?Amarogentin achieves this potential selectivity by small, yet significant, structural differences inherent to the binding cavities of the two isoforms.?Hypothetically, it might block the entry of the natural substrates in the hydrophobic binding channel of the COX-2, inhibiting the cyclooxygenation step[1].