Chaurasiya Narayan D, Gogineni Vedanjali, Elokely Khaled M, León Francisco, Núñez Marvin J, Klein Michael L, Walker Larry A, Cutler Stephen J, Tekwani Babu L
Institute for Computational Molecular Science and Department of Chemistry, Temple University , Philadelphia, Pennsylvania 19122, United States.
Department of Pharmaceutical Chemistry, Tanta University , Tanta 31527, Egypt.
J Nat Prod. 2016 Oct 28;79(10):2538-2544. doi: 10.1021/acs.jnatprod.6b00440. Epub 2016 Oct 18.
Calea urticifolia (Asteraceae: Asteroideae) has long been used as a traditional medicine in El Salvador to treat arthritis and fever, among other illnesses. The chloroform extract of the leaves of C. urticifolia showed potent inhibition of recombinant human monoamine oxidases (MAO-A and -B). Further bioassay-guided fractionation led to the isolation of a flavonoid, acacetin, as the most prominent MAO inhibitory constituent, with IC values of 121 and 49 nM for MAO-A and -B, respectively. The potency of MAO inhibition by acacetin was >5-fold higher for MAO-A (0.121 μM vs 0.640 μM) and >22-fold higher for MAO-B (0.049 μM vs 1.12 μM) as compared to apigenin, the closest flavone structural analogue. Interaction and binding characteristics of acacetin with MAO-A and -B were determined by enzyme-kinetic assays, enzyme-inhibitor complex binding, equilibrium-dialysis dissociation analyses, and computation analysis. Follow-up studies showed reversible binding of acacetin with human MAO-A and -B, resulting in competitive inhibition. Acacetin showed more preference toward MAO-B than to MAO-A, suggesting its potential for eliciting selective pharmacological effects that might be useful in the treatment of neurological and psychiatric disorders. In addition, the binding modes of acacetin at the enzymatic site of MAO-A and -B were predicted through molecular modeling algorithms, illustrating the high importance of ligand interaction with negative and positive free energy regions of the enzyme active site.
荨麻叶卡利亚菊（菊科：紫菀亚科）在萨尔瓦多长期被用作传统药物，用于治疗关节炎、发烧及其他疾病。荨麻叶卡利亚菊叶子的氯仿提取物对重组人单胺氧化酶（MAO-A和MAO-B）显示出强效抑制作用。进一步的生物活性导向分离得到一种黄酮类化合物刺槐素，它是最主要的MAO抑制成分，对MAO-A和MAO-B的IC值分别为121 nM和49 nM。与最接近的黄酮结构类似物芹菜素相比，刺槐素对MAO-A的抑制效力高5倍以上（0.121 μM对0.640 μM），对MAO-B的抑制效力高22倍以上（0.049 μM对1.12 μM）。通过酶动力学测定、酶-抑制剂复合物结合、平衡透析解离分析和计算分析，确定了刺槐素与MAO-A和MAO-B的相互作用及结合特性。后续研究表明，刺槐素与人MAO-A和MAO-B的结合是可逆的，导致竞争性抑制。刺槐素对MAO-B的偏好高于MAO-A，表明其可能具有引发选择性药理作用的潜力，这可能对治疗神经和精神疾病有用。此外，通过分子建模算法预测了刺槐素在MAO-A和MAO-B酶活性位点的结合模式，说明了配体与酶活性位点正负自由能区域相互作用的高度重要性。
