Grupo de Bioquímica Teórica, Universidad Industrial de Santander, Cra. 27 Calle 9, Bucaramanga, Colombia.
J Mol Model. 2021 Jun 11;27(7):198. doi: 10.1007/s00894-021-04808-y.
The selective N-acylation of 1,2-amino alcohols has been proposed to occur through the proton shuttle mechanism. However, the O-acetylation of propranolol catalyzed by Candida antarctica lipase B is an exception. We investigated the relation between the chemoselectivity of this reaction and the acyl group length. For this purpose, we compared the acyl groups: ethanoyl, butanoyl, octanoyl, and hexadecanoyl. We studied the Michaelis complexes between serine-acylated Candida antarctica lipase B and propranolol, employing a computational approach that involved sampling Michaelis complex conformations through ensemble docking plus consensus scoring and molecular dynamics simulations. The conformations were then classified as near attack conformations for acylation of the amino or hydroxy group. The relative populations of these two classes of conformations were found to be consistent with the experimentally observed chemoselective O-acetylation. We predict that increasing the length of the hydrocarbon chain of the acyl group will cause O-acylation to be unfavorable with respect to N-acylation. The nucleophilic attack of propranolol to the acylated lipase was found to be more favorable through the classical mechanism when compared with the proton shuttle mechanism.
1,2-氨基醇的选择性 N-酰化被认为是通过质子转移机制发生的。然而，南极假丝酵母脂肪酶 B 催化的普萘洛尔的 O-乙酰化是一个例外。我们研究了该反应的化学选择性与酰基长度之间的关系。为此，我们比较了酰基：乙酰基、丁酰基、辛酰基和十六烷酰基。我们通过包含集合对接加共识评分和分子动力学模拟的组合来研究丝氨酸酰化的南极假丝酵母脂肪酶 B 与普萘洛尔之间的迈克尔利斯复合物，以考察其与普萘洛尔的迈克尔利斯复合物构象。然后将这些构象分类为用于酰化氨基或羟基的接近攻击构象。发现这两种构象类别的相对丰度与实验观察到的化学选择性 O-乙酰化一致。我们预测，随着酰基的烃链长度的增加，O-酰化相对于 N-酰化将变得不利。与质子转移机制相比，通过经典机制，发现普萘洛尔对酰化脂肪酶的亲核攻击更有利。
