mMGL Inhibitors

Chemical inhibitors of mMGL can be understood through their interactions with various components of lipid metabolism and hydrolysis pathways, which are intrinsically connected to the functionality of mMGL. Orlistat and its bioactive form Tetrahydrolipstatin target gastric and pancreatic lipases, leading to a reduction in the breakdown of fats, which results in lower availability of fatty acids that could serve as substrates for mMGL. This reduced availability of substrates can indirectly inhibit the catalytic activity of mMGL by simply limiting its potential action on lipid substrates. Similarly, Ebelactone A and Ebelactone B, by inhibiting esterases and lipases, prevent the hydrolysis of fats, which again leads to a decrease in fatty acid substrates for mMGL.

Furthermore, inhibitors targeting other enzymes in lipid metabolism can indirectly influence mMGL activity. For example, JZL184 and URB602 are selective inhibitors of monoacylglycerol lipase, an enzyme that could compete with mMGL for substrates. By inhibiting this enzyme, these chemicals can reduce competition for monoacylglycerols, thereby limiting the activity of mMGL on these substrates. MAFP and PF-3845, as inhibitors of fatty acid amide hydrolase, can lower the levels of fatty acids, thus indirectly inhibiting mMGL by reducing the pool of substrates it can act upon. WWL70 blocks alternative lipid metabolism pathways, which may lead to a decrease in available substrates for mMGL action. RHC80267 and SA57, which inhibit diacylglycerol lipase, limit the production of monoacylglycerols, a substrate class for mMGL, thus potentially reducing mMGL activity by substrate scarcity. Through these mechanisms, the selected chemicals collectively contribute to a decrease in mMGL activity by altering the availability and competition for its substrates within the lipid metabolism network.