Laboratorio de Cultivo Celular, Sección de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Salvador Díaz Mirón Esq. Plan de San Luis s/n, Casco de Santo Tomas, Miguel Hidalgo, Mexico City 11340, Mexico.
Department of Organic and Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw, Banacha 1, 02-091 Warsaw, Poland.
Molecules. 2023 Jan 6;28(2):576. doi: 10.3390/molecules28020576.
Lower activity of the histaminergic system is associated with neurological disorders, including Alzheimer's disease (AD). Thus, the enhancement of histaminergic neurotransmission by inhibition of histamine -methyl transferase (HNMT), which degrades histamine, appears as an important approach. For this purpose, rigid and flexible molecular docking studies of 185 FDA-approved drugs with the HNMT enzyme were carried out to select two compounds to perform molecular dynamics (MD) simulations to evaluate the binding free energies and stability of the enzyme-drug complexes. Finally, an HNMT inhibition assay was performed to corroborate their effect towards HNMT. Molecular docking studies with HNMT allowed the selection of dihydroergotamine and vilazodone since these molecules showed the lowest Gibbs free energy values. Analysis of the binding mode of vilazodone showed interactions with the binding pocket of HNMT with Glu28, Gln143, and Asn283. In contrast, dihydroergotamine binds to the HNMT active site in a different location, apparently because it is overall the more rigid ligand compared to flexible vilazodone. HNMT inhibitory activity for dihydroergotamine and vilazodone was corroborated (IC = 72.89 μM and 45.01 μM, respectively) by in vitro assays. Drug repurposing of HNMT was achieved by employing computational studies.
组胺能系统活性降低与包括阿尔茨海默病（AD）在内的神经紊乱有关。因此，通过抑制组胺-N-甲基转移酶（HNMT）来增强组胺能神经传递，作为一种重要的方法出现了。为此，对 185 种经美国食品和药物管理局批准的药物与 HNMT 酶进行了刚性和柔性分子对接研究，以选择两种化合物进行分子动力学（MD）模拟，以评估酶-药物复合物的结合自由能和稳定性。最后，进行了 HNMT 抑制测定以证实它们对 HNMT 的作用。与 HNMT 的分子对接研究允许选择二氢麦角胺和维拉佐酮，因为这些分子显示出最低的吉布斯自由能值。对维拉佐酮结合模式的分析表明，它与 HNMT 的结合口袋中的 Glu28、Gln143 和 Asn283 相互作用。相比之下，二氢麦角胺以不同的位置结合到 HNMT 的活性部位，显然是因为与灵活的维拉佐酮相比，它是整体上更刚性的配体。通过体外测定证实了二氢麦角胺和维拉佐酮对 HNMT 的抑制活性（IC = 72.89 μM 和 45.01 μM）。通过计算研究实现了 HNMT 的药物再利用。
