Etnalead s.r.l., c/o EtnaBuilding, Scuola Superiore di Catania, Università degli Studi di Catania , via S. Nullo 5/i, I-95123 Catania, Italy.
J Chem Inf Model. 2014 Apr 28;54(4):1200-7. doi: 10.1021/ci400346k. Epub 2014 Apr 2.
Imidazoline ligands in I2-type binding sites in the brain alter monoamine turnover and release. One example of an I2 binding site characterized by binding studies, kinetics, and crystal structure has been described in monoamine oxidase B (MAO B). MAO A also binds imidazolines but has a different active site structure. Docking and molecular dynamics were used to explore how 2-(2-benzofuranyl)-2-imidazoline hydrochloride (2-BFI) binds to MAO A and to explain why tranylcypromine increases tight binding to MAO B. The energy for 2-BFI binding to MAO A was comparable to that for tranylcypromine-modified MAO B, but the location of 2-BFI in the MAO A could be anywhere in the monopartite substrate cavity. Binding to the tranylcypromine-modified MAO B was with high affinity and in the entrance cavity as in the crystal structure, but the energies of interaction with the native MAO B were less favorable. Molecular dynamics revealed that the entrance cavity of MAO B after tranylcypromine modification is both smaller and less flexible. This change in the presence of tranylcypromine may be responsible for the greater affinity of tranylcypromine-modified MAO B for imidazoline ligands.
脑内 I2 型结合部位的咪唑啉配体改变单胺类递质的代谢和释放。通过结合研究、动力学和晶体结构已经描述了单胺氧化酶 B（MAO B）中一种具有特征的 I2 结合部位。MAO A 也结合咪唑啉，但具有不同的活性部位结构。通过对接和分子动力学研究，探讨了 2-(2-苯并呋喃基)-2-咪唑啉盐酸盐（2-BFI）与 MAO A 的结合方式，并解释了为什么反苯环丙胺能增加与 MAO B 的紧密结合。2-BFI 与 MAO A 的结合能与反苯环丙胺修饰的 MAO B 相当，但 2-BFI 在 MAO A 中的位置可以在单部分底物腔的任何位置。与反苯环丙胺修饰的 MAO B 的结合具有高亲和力，并位于晶体结构中的入口腔中，而与天然 MAO B 的相互作用能则不太有利。分子动力学揭示，反苯环丙胺修饰后 MAO B 的入口腔更小，灵活性更低。在反苯环丙胺存在的情况下，这种变化可能是反苯环丙胺修饰的 MAO B 对咪唑啉配体具有更高亲和力的原因。
