A molecular modeling study on the enantioselectivity of aryl alkyl ketone reductions by a NADPH-dependent carbonyl reductase
A molecular modeling study on the enantioselectivity of aryl alkyl ketone reductions by a NADPH-dependent carbonyl reductase
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DOI：
10.1007/s00894-007-0168-9
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发表时间：
2007-02
影响因子：
2.2
通讯作者：
T. Cundari;Adriana Dinescu;Dunming Zhu;L. Hua
中科院分区：
文献类型：
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作者：
T. Cundari;Adriana Dinescu;Dunming Zhu;L. Hua
对沙门氏菌孢子菌的彩色羰基还原酶（SSCR）的自动结构分析表明，两个最大的潜在受体位点位于烟酰胺还原剂附近。最大的受体位点是边长为~ 8 Å × 9 Å × 13 Å的不等边三角形，宽度较窄；一个角被亲水残基包围，亲水残基有利于与酮氧结合。对接芳基烷基酮显示出与最大受体位点结合的明显偏好，以及将底物的羰基氧置于最大受体位点的亲水角的构象。芳基烷基酮的有利对接构象分为两个低能系综。这些构象组合是通过取代基的位置来区分的，在烟酰胺还原剂面前呈现酮的i面或re面。对于本文研究的酮类，在所有情况下，由酮还原得到的醇的主要对映体与与受体位点具有最稳定相互作用能的构象之间存在对应关系。受体位点建模、对接模拟、分子动力学和酶-底物几何优化导致了一个模型，用于理解这种nadph依赖性羰基还原酶的对映选择性。nadph依赖性羰基还原酶的受体位点模型
Automated structural analysis ofSporobolomyces salmonicolorcarbonyl reductase (SSCR) indicates that the two largest potential receptor sites are in the vicinity of the nicotinamide reductant. The largest receptor site is a scalene triangle with sides of ∼8 Å by 9 Å by 13 Å, which is narrow in width; one corner is surrounded by hydrophilic residues that can favorably bond with the ketone oxygen. Docking aryl alkyl ketones shows a distinct preference for binding to the largest receptor site, and for conformations that place the carbonyl oxygen of the substrate in the hydrophilic corner of the largest receptor site. Favorable docking conformations for aryl alkyl ketones fall into two low-energy ensembles. These conformational ensembles are distinguished by the positions of the substituents, presenting either theSi-orRe-face of the ketone to the nicotinamide reductant. For the ketones investigated here, there is a correspondence between the major enantiomer of the alcohol obtained from the reduction of the ketone and the conformer found to have the most stable interaction energy with the receptor site in all cases. The receptor site modeling, docking simulations, molecular dynamics, and enzyme-substrate geometry optimizations lead to a model for understanding the enantioselectivity of this NADPH-dependent carbonyl reductase.FigureReceptor site model for NADPH-dependent carbonyl reductase