Tuccinardi Tiziano, Granchi Carlotta, Rizzolio Flavio, Caligiuri Isabella, Battistello Vittoria, Toffoli Giuseppe, Minutolo Filippo, Macchia Marco, Martinelli Adriano
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Department of Pharmacy, University of Pisa, 56126 Pisa, Italy.
Bioorg Med Chem. 2014 Jul 1;22(13):3285-91. doi: 10.1016/j.bmc.2014.04.057. Epub 2014 May 6.
Monoacylglycerol lipase is a serine hydrolase that play a major role in the degradation of 2-arachidonoylglycerol, an endocannabinoid neurotransmitter implicated in several physiological processes. Recent studies have shown the possible role of MAGL inhibitors as anti-inflammatory, anti-nociceptive and anti-cancer agents. The use of irreversible MAGL inhibitors determined an unwanted chronic MAGL inactivation, which acquires a functional antagonism function of the endocannabinoid system. However, the application of reversible MAGL inhibitors has not yet been explored, mainly due to the scarcity of known compounds possessing efficient reversible inhibitory activities. In this study we reported the first virtual screening analysis for the identification of reversible MAGL inhibitors. Among the screened compounds, the (4-(4-chlorobenzoyl)piperidin-1-yl)(4-methoxyphenyl)methanone (CL6a) is a promising reversible MAGL inhibitor lead (Ki=8.6μM), which may be used for the future development of a new class of MAGL inhibitors. Furthermore, the results demonstrate the validity of the methodologies that we followed, encouraging additional screenings of other commercial databases.
单酰甘油脂肪酶是一种丝氨酸水解酶，在2-花生四烯酸甘油酯（一种参与多种生理过程的内源性大麻素神经递质）的降解中起主要作用。最近的研究表明，单酰甘油脂肪酶抑制剂可能具有抗炎、抗痛觉过敏和抗癌作用。使用不可逆的单酰甘油脂肪酶抑制剂会导致不必要的慢性单酰甘油脂肪酶失活，从而对内源性大麻素系统产生功能性拮抗作用。然而，可逆性单酰甘油脂肪酶抑制剂的应用尚未得到探索，主要原因是具有有效可逆抑制活性的已知化合物稀缺。在本研究中，我们报告了首次用于鉴定可逆性单酰甘油脂肪酶抑制剂的虚拟筛选分析。在筛选出的化合物中，（4-（4-氯苯甲酰基）哌啶-1-基）（4-甲氧基苯基）甲酮（CL6a）是一种有前景的可逆性单酰甘油脂肪酶抑制剂先导物（Ki = 8.6μM），可用于未来开发新型单酰甘油脂肪酶抑制剂。此外，结果证明了我们所采用方法的有效性，这鼓励对其他商业数据库进行更多筛选。
