Laboratory of Theoretical and Computational Chemistry, Institute of Theoretical Chemistry, College of Chemistry, Jilin University, Changchun 130023, China.
College of Biology and Food Engineering, Jilin Engineering Normal University, Changchun 130052, China.
Molecules. 2022 Nov 3;27(21):7512. doi: 10.3390/molecules27217512.
Monoacylglycerol lipase (MAGL) can regulate the endocannabinoid system and thus becomes a target of antidepressant drugs. In this paper, molecular docking and molecular dynamics simulations, combined with binding free energy calculation, were employed to investigate the inhibitory mechanism and binding modes of four aryl formyl piperidine derivative inhibitors with different 1-substituents to MAGL. The results showed that in the four systems, the main four regions where the enzyme bound to the inhibitor included around the head aromatic ring, the head carbonyl oxygen, the tail amide bond, and the tail benzene ring. 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 of 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. If the swing is large enough, it can weaken the binding strength of the head carbonyl oxygen to its nearby residues, and even the whole inhibitor with the enzyme so that the inhibition decreases.
单酰基甘油脂肪酶（MAGL）可以调节内源性大麻素系统，因此成为抗抑郁药物的靶点。在本文中，采用分子对接和分子动力学模拟，并结合结合自由能计算，研究了四种芳基甲酰哌啶衍生物抑制剂与 MAGL 的不同 1-取代基的抑制机制和结合模式。结果表明，在四个体系中，酶与抑制剂结合的主要四个区域包括头部芳环周围、头部羰基氧、尾部酰胺键和尾部苯环。由于抑制剂的 1-取代基的差异，酶的更灵活的盖子结构域发生了显著的构象变化，导致抑制剂的尾部发生不同程度的翻转。这种翻转导致尾部酰胺键的方向不同，与酶中一些带电残基的相互作用发生了更大的变化，这进一步导致了尾部苯环的不同摆动。如果摆动足够大，它可以削弱头部羰基氧与其附近残基的结合强度，甚至使整个抑制剂与酶结合，从而降低抑制作用。
