Organisch-Chemisches Institut, Westfälische Wilhelms-Universität Münster, Corrensstraße 40, 48149 Münster, Germany.
Department of Drug Design and Optimization, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS) - Helmholtz Centre for Infection Research (HZI), University Campus E8.1, 66123 Saarbrücken, Germany.
J Med Chem. 2020 Jun 11;63(11):6225-6237. doi: 10.1021/acs.jmedchem.0c00648. Epub 2020 May 22.
Matrix metalloproteinases (MMPs) are involved in a spectrum of physiological processes, rendering them attractive targets for small-molecule drug discovery. Strategies to achieve selective inhibition continue to be intensively pursued, facilitated by advances in structural biology. Herein, we harness MMPs 2, 8, 9, and 13 to validate the difluoro motif as a hybrid bioisostere of CF and Et (BITE) in a series of modified barbiturate inhibitors. Crystallographic analyses of representative structures reveal conformations of the difluoro motif that manifest stabilizing hyperconjugative interactions consistent with the stereoelectronic effect. Detailed docking studies of a potent difluorinated probe with MMP-9 are also disclosed and indicate that the structural basis of inhibition is a consequence of the anisotropic nature of the motif. Significant selectivity of MMP 13 versus MMP-2 can be achieved by subtle chain contraction in a BITE-modified inhibitor.
基质金属蛋白酶（MMPs）参与了一系列生理过程，因此成为小分子药物发现的有吸引力的靶标。通过结构生物学的进步，继续积极追求实现选择性抑制的策略。在此，我们利用 MMPs2、8、9 和 13 来验证二氟基作为 CF 和 Et（BITE）的混合生物等排物的一系列修饰巴比妥抑制剂中的融合生物等排物。代表性结构的晶体学分析揭示了二氟基的构象，表现出与立体电子效应一致的稳定超共轭相互作用。还披露了与 MMP-9 的强效二氟化探针的详细对接研究，并表明抑制的结构基础是该基序各向异性的结果。通过 BITE 修饰抑制剂中链的细微收缩，可以实现 MMP-13 对 MMP-2 的显著选择性。
