a Department of Pharmacy , University of Pisa , Pisa , Italy.
b Pathology Unit, Department of Molecular Biology and Translational Research , National Cancer Institute and Center for Molecular Biomedicine , Aviano , Italy.
J Enzyme Inhib Med Chem. 2019 Dec;34(1):589-596. doi: 10.1080/14756366.2019.1571271.
Monoacylglycerol lipase (MAGL) is an attractive therapeutic target for many pathologies, including neurodegenerative diseases, cancer as well as chronic pain and inflammatory pathologies. The identification of reversible MAGL inhibitors, devoid of the side effects associated to prolonged MAGL inactivation, is a hot topic in medicinal chemistry. In this study, a novel phenyl(piperazin-1-yl)methanone inhibitor of MAGL was identified through a virtual screening protocol based on a fingerprint-driven consensus docking (CD) approach. Molecular modeling and preliminary structure-based hit optimization studies allowed the discovery of derivative 4, which showed an efficient reversible MAGL inhibition (IC = 6.1 µM) and a promising antiproliferative activity on breast and ovarian cancer cell lines (IC of 31-72 µM), thus representing a lead for the development of new and more potent reversible MAGL inhibitors. Moreover, the obtained results confirmed the reliability of the fingerprint-driven CD approach herein developed.
单酰基甘油脂肪酶（MAGL）是许多病理学的有吸引力的治疗靶点，包括神经退行性疾病、癌症以及慢性疼痛和炎症性疾病。寻找无延长 MAGL 失活相关副作用的可逆 MAGL 抑制剂是药物化学领域的热门话题。在这项研究中，通过基于基于指纹的共识对接（CD）方法的虚拟筛选方案，鉴定出了一种新型的苯（哌嗪-1-基）甲酮 MAGL 抑制剂。分子建模和初步基于结构的命中优化研究发现了衍生物 4，它显示出有效的可逆 MAGL 抑制作用（IC = 6.1 μM），并对乳腺癌和卵巢癌细胞系具有有前景的抗增殖活性（IC 为 31-72 μM），因此代表了开发新型和更有效的可逆 MAGL 抑制剂的先导化合物。此外，所得结果证实了本文所开发的基于指纹的 CD 方法的可靠性。
