Insight Into The Inhibitory Mechanism Of Aryl Formyl Piperidine Derivatives On Monoacylglycerol Lipase Through Molecular Dynamics Simulations

In recent years,the incidence of depression has been on the rise both nationally and internationally due to a few genetic,psychological,and social factors,which have attracted a great deal of scientific attention.Currently,the main antidepressants are selective pentraxin reuptake inhibitors,tricyclic antidepressants,monoamine oxidase inhibitors,and norepinephrine reuptake inhibitors,but the pathogenesis of depression is not clearly understood,which makes the development of subsequent specific drugs difficult.Several recent studies have shown that dysregulation of endocannabinoids is closely related to the pathology of depression.Monoacylglycerol lipase in the endocannabinoid system is the key enzyme in the hydrolysis of the endocannabinoid 2-arachidonoyglycerol.Therefore,monoacylglycerol lipase emerges as a potential therapeutic target for the treatment of depression,providing a viable direction for the design of future antidepressant drugs.Recently,a series of competitive inhibitors of aryl formyl piperidine derivatives were designed in the experiment for monoacylglycerol lipase,which significantly improved the depressive behaviour induced by reserpine.The permanent blockade of monoacylglycerol lipase activity by irreversible inhibitors results in the continued activation of cannabinoid receptor 1,which may cause side effects,whereas aryl formyl piperidine derivatives temporarily inhibit the enzyme activity in a reversible manner,thereby reducing the incidence of side effects.The mechanism of molecular inhibition between monoacylglycerol lipase and aryl formyl piperidine derivatives is currently unknown.In this paper,molecular docking,molecular dynamics simulations,and binding free energy calculations were used to investigate the binding patterns and the mechanisms underlying the different inhibitory effects of four aryl formyl piperidine derivative inhibitors with different 1-substituted groups on monoacylglycerol lipase.The results show that the four aryl formyl piperidine derivative inhibitors can be stably bound within the hydrophobic pocket behind the lid domain,impeding the binding and hydrolysis of the natural substrate and acting as competitive inhibitors.In all four complex systems,the main four regions where the enzyme bound to the inhibitor included near the aromatic ring of the inhibitor head,near the carbonyl oxygen of the inhibitor head,near the amide bond of the inhibitor tail,and near the benzene ring of the inhibitor tail.The calculations of binding free energy for the decomposition of the residues as a unit show that the residues in the region near the tail amide bond have the greatest difference between the four complex systems.Combined with the conformational analysis,it is clear that the significant conformational changes in the more flexible lid domain of the enzyme were caused by 1-substituted group differences of inhibitors and resulted in different degrees of flipping in the tail of the inhibitor.The flipping led to a different direction for the tail amide bond and made a greater variation in its interaction with some of the charged residues in the enzyme,which further contributed to a different swing of the tail benzene ring.Some of these cause swings of greater magnitude and consequently weaken the binding strength of the head carbonyl oxygen to nearby proteins(the region where all enzyme-inhibitor interactions are strongest),resulting in a weakening of the overall binding free energy and a corresponding weakening of the inhibitory capacity.The key residues identified in this work that cause the tail flip of the inhibitor are mainly Phe159,Ile179,Arg202,and Tyr194.When the inhibitor binds to the active site of the enzyme,the conformations of these four residues undergo a series of changes,leading to a change in the hydrophilic and hydrophobic environment and hydrogen bonding network,thus explaining in detail the reason for the tail flip of the inhibitor.In conclusion,the results obtained in the study can provide some theoretical guidance for the design of monoacylglycerol lipase inhibitors.