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首页> 外文期刊>RSC Advances >Kinetic resolution of (RS)-1-chloro-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol: a metoprolol intermediate and its validation through homology model of Pseudomonas fluorescens lipase
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Kinetic resolution of (RS)-1-chloro-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol: a metoprolol intermediate and its validation through homology model of Pseudomonas fluorescens lipase

机译：（ RS ）-1-氯-3-（4-（2-甲氧基乙基）苯氧基）丙-2-醇的动力学拆分：美托洛尔中间体及其通过假单胞菌同源性模型的验证荧光脂酶

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In the present study Pseudomonas fluorescens lipase (PFL) was screened as a time efficient biocatalyst for the kinetic resolution of a racemic intermediate [(RS)-1-chloro-3-(4-(2-methoxyethyl)phenoxy)propan-2-ol] of metoprolol, an important selective β1-blocker drug. PFL selectively acylated the R-form of this racemic intermediate in a short duration of 3 h. Different reaction parameters were optimized to achieve maximum enantioselectivity. It was found that at 30 °C, enzyme activity of 400 units and substrate concentration of 10 mM gave a high enantioselectivity and conversion in an optimum time of 3 hours (C = 50.5%, eep = 97.2%, ees = 95.4%, E = 182). To validate these experimental results, the 3D structure of PFL was built using homology modelling. Validation of the model through Ramachandran plot (92.7% in favored region), Errat plot (overall quality factor, 79.27%), Verify-3D score (86.19) and ProSA_Z score (?6.24) depicted the overall good quality of the model. Molecular docking of the R- and S-enantiomers of the intermediate, which was performed on this model, demonstrated a strong H-bond interaction (1.6 ?) between the hydroxyl group of the R-enantiomer and Arg54, a key binding residue of the catalytic site of PFL, while no significant interaction with the S-enantiomer was observed. Thus, the outcome of this docking study was in agreement with the experimental data, clarifying that PFL preferentially catalysed the transesterification of the R-enantiomer into the corresponding ester, leaving the S-enantiomer intact.
机译：在本研究中，筛选了荧光假单胞菌脂肪酶（PFL）作为消旋中间体[（ RS ）-1-chloro-3-的动力学拆分的高效时间生物催化剂。美托洛尔的（4-（2-甲氧基乙基）苯氧基）丙-2-醇]，一种重要的选择性β 1 阻滞剂。 PFL在短短3小时内选择性地酰化该消旋中间体的 R -形式。优化了不同的反应参数以实现最大对映选择性。结果发现，在30°C下，酶活性为400单位，底物浓度为10 mM，在3小时的最佳时间（ C = 50.5％，ee p = 97.2％，ee s = 95.4％， E = 182）。为了验证这些实验结果，使用同源性建模建立了PFL的3D结构。通过Ramachandran图（在有利区域中为92.7％），Errat图（总体品质因数为79.27％），Verify-3D分数（86.19）和ProSA_ Z 分数（？6.24）对模型进行验证。模型整体质量不错。在此模型上进行的中间体 R -和 S -对映体的分子对接表明，羟基之间存在很强的H键相互作用（1.6？）的 R -对映体和Arg54（PFL催化位点的关键结合残基），但未观察到与 S -对映体的显着相互作用。因此，该对接研究的结果与实验数据相符，阐明了PFL优先催化 R -对映异构体酯交换成相应的酯，剩下 S -对映体完整。

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