Evaluation of Inhibitory Activities of 236 Marine Microbial Metabolites against Acetylcholinesterase and α-Glucosidase
Yan Liu, Shuai Liu, Xin Liu, Yura Ha, Cangzhu Sun, Wenwen Yi, Le Qin, Kuo Yong, Mengxuan Chen, Mingzhu Ma, Tengfei Song, Sidra Kaleem, Qiao Li, Xiufang Zhang, Xiao-Yuan Lian, Zhizhen ZhangBackground:
Acetylcholinesterase (AChE) and alpha-glucosidase (AG) inhibitors have been used clinically for the treatment of Alzheimer's disease (AD) and diabetes mellitus (DM), respectively. However, the AChE and AG inhibitors used currently have shown limited efficacy with serious side effects. It is important to discover novel AChE and AG inhibitors for AD and DM therapy. This study aims to evaluate the inhibitory activity of 236 marine microbial metabolites against AChE and AG, to identify new AChE and AG inhibitors that can serve as potential lead compounds for the discovery and development of new drugs.
Methods:
The 236 compounds at a concentration of 100 μM were initially assayed for their inhibitory activities against AChE and AG. Then, the active compounds with inhibition rates of over 50.00% were further tested to obtain their IC50 values. Molecular docking was performed to predict the binding modes and interaction sites of the active compounds with AChE and AG.
Results:
The AChE and AG inhibitory activity assay identified 11 AChE inhibitors and 23 AG inhibitors with inhibitory rates of over 50%. Lumichrome (173) and tetracyclic thiazinogeldanamycin (195) exhibited the most AChE inhibitory activity with IC50 values of 10.69 and 9.74 μM. Peniresorcinoside A (72), phthalimidinic acid A (104), 2-hydroxyemodic acid (105), asperthecin (106), versicolorin B (107), actinomycin D (138), actinomycin V (139), and 1-linoleylglycerol (191) showed potent AG inhibitory activity with IC50 values of 0.96–8.41 μM. 1-Linoleylglycerol (191) had inhibitory activity on both AChE and AG. Molecular docking predicted potential binding modes and interaction sites for several active compounds with AChE and AG.
Conclusion:
This study identified 11 AChE inhibitors and 23 AG inhibitors, each with distinct structural types. Lumichrome (173), tetracyclic thiazinogeldanamycin (195), and aurantiamide (236) were three AChE inhibitors with potential pharmaceutical and clinical benefits that warrant further investigation. Some AG inhibitors with structures different from those currently used showed potent activities, stronger than or very close to those of the positive controls miglitol and voglibose. All successfully docked AG inhibitors formed hydrogen bonds with GLU A:748, the core catalytic residue in the AG active pocket. Further investigation should focus on some potent new AChE and AG inhibitors.