Tung_2021_RSC.Adv_11_31062

Monoacylglycerol lipase (MAGL), a serine hydrolase, converts endocannabinoid 2-arachidonoylglycerol (2-AG) to arachidonic acid (AA) and glycerol in the brain and plays a bidirectional role in controlling nueroinflammation. MAGL, involved in Alzheimer's and Parkinson's diseases, is a promising target for treatment of neurodegenerative disorders. However, the irreversible inhibitors of MAGL lead to the desensitization of CB1 receptors further impairing the benefits associated with the indirect CB1 stimulation. Therefore, development of potent reversible inhibitors from natural products (NPs) and traditional chinese medicines (TCMs) are safer and free from adverse side effects and feasible to avoid drawbacks which irreversible inhibitors cause. Here, we employed pharmacophore-based screening of drug candidates coupled with molecular docking, biochemical assay and Ligplot analyses to identify and characterize inhibitors targeting human MAGL (hMAGL). The built pharmacophore model, Phar-MAGL successfully identified inhibitors NP-2 (IC(50) = 9.5 +/- 1.2 microM), NP-5 (IC(50) = 14.5 +/- 1.3 microM), and NP-3 (IC(50) = 15.2 +/- 1.4 microM), which apparently attenuated the activities of hMAGL in vitro. The evident activities of the identified inhibitors against hMAGL showed that the pharmacophore model, Phar-MAGL is reliable and efficient in screening inhibitors against hMAGL. Our study successfully identified a natrual product inhibitor, NP-2 (8-PN), from the plant Humulus lupulus L. (hops) and its positive effects in neurogenesis and neurodifferentiation along with the evident inhibitory potency against hMAGL revealed the potential for further optimizing and developing into drugs to treat neuroinflammation, Alzheimer's and Parkinson's diseases.