Peón Antonio, Robles Adrián, Blanco Beatriz, Convertino Marino, Thompson Paul, Hawkins Alastair R, Caflisch Amedeo, González-Bello Concepción
Centro Singular de Investigación en Química Biolóxica e Materiais Moleculares, CIQUS, and Departamento de Química Orgánica, Universidade de Santiago de Compostela, calle Jenaro de la Fuente s/n, 15782, Santiago de Compostela, Spain.
Department of Biochemistry, University of Zurich, 8057, Zurich, Switzerland.
ChemMedChem. 2017 Sep 21;12(18):1512-1524. doi: 10.1002/cmdc.201700396. Epub 2017 Sep 12.
A multidisciplinary approach was used to identify and optimize a quinazolinedione-based ligand that would decrease the flexibility of the substrate-covering loop (catalytic loop) of the type II dehydroquinase from Helicobacter pylori. This enzyme, which is essential for the survival of this bacterium, is involved in the biosynthesis of aromatic amino acids. A computer-aided fragment-based protocol (ALTA) was first used to identify the aromatic fragments able to block the interface pocket that separates two neighboring enzyme subunits and is located at the active site entrance. Chemical modification of its non-aromatic moiety through an olefin cross-metathesis and Seebach's self-reproduction of chirality synthetic principle allowed the development of a quinazolinedione derivative that disables the catalytic loop plasticity, which is essential for the enzyme's catalytic cycle. Molecular dynamics simulations revealed that the ligand would force the catalytic loop into an inappropriate arrangement for catalysis by strong interactions with the catalytic tyrosine and by expelling the essential arginine out of the active site.
采用多学科方法来鉴定和优化一种基于喹唑啉二酮的配体，该配体将降低幽门螺杆菌II型脱氢喹酶底物覆盖环（催化环）的灵活性。这种对该细菌生存至关重要的酶参与芳香族氨基酸的生物合成。首先使用基于计算机辅助片段的方案（ALTA）来鉴定能够阻断位于活性位点入口处、分隔两个相邻酶亚基的界面口袋的芳香族片段。通过烯烃复分解对其非芳香部分进行化学修饰以及基于Seebach手性合成原理的自我复制，使得能够开发出一种喹唑啉二酮衍生物，该衍生物会使对酶催化循环至关重要的催化环可塑性丧失。分子动力学模拟表明，该配体将通过与催化酪氨酸的强相互作用以及将必需的精氨酸排出活性位点，迫使催化环进入不利于催化的不合适排列。
