Correlation Between In Silico Docking/Simulation Results and In Vitro MAGL Inhibition Potency of Selected Triterpenes.

Monoacylglycerol lipase (MAGL) degrades the endocannabinoid 2-arachidonyl glycerol. MAGL inhibitors, such as the triterpene pristimerin, alleviate neuropathic pain in animal models. In silico studies were carried out using SwissDock, PyRx-0.8 and CB-Dock2, to check if they correlated with the in vitro MAGL inhibition potency of various triterpenes. In terms of affinity, free energy of binding and docking scores to MAGL, pristimerin (52.75, -9.32, -10.83, and -11.5 kcal/mol) was better than euphol (44.86, -8.49, -9.56, and -10.7 kcal/mol), which in turn was better than β-amyrin (35.17, -7.37, -8.21, and -8.8 kcal/mol). Finally, β-amyrin was better than or equal to α-amyrin (35.10, -7.19, -7.95, and -8.6 kcal/mol). In molecular dynamic simulations (MDSs), pristimerin exhibited the highest stability and reached the steady state after 20 ns with the lowest root mean square fluctuation (RMSF) at the binding site, compared to the triterpenes. The reported half maximal inhibitory concentration (IC₅₀) values of recombinant human and rat MAGL inhibition were in the following order: α-amyrin > β-amyrin > euphol > pristimerin. Linear regression analysis showed that the affinity, free energy of binding, and docking scores significantly correlated with the IC₅₀ of MAGL inhibition. Amongst the triterpenes studied, pristimerin was the most potent inhibitor of MAGL and also had the highest affinity in the in silico studies. Thus, molecular docking and MDS results correlated with the potency of triterpenes inhibiting MAGL activity in vitro and could be used for screening of triterpenes prior to experimental validation.