Christian Doppler Laboratory for High-Content Structural Biology and Biotechnology, Department of Structural and Computational Biology, University of Vienna , Campus Vienna Biocenter 5, A-1030 Vienna, Austria.
Boehringer Ingelheim RCV GmbH & Co. KG , Dr.-Boehringer-Gasse 5-11, A-1121 Vienna, Austria.
J Med Chem. 2017 Nov 9;60(21):8708-8715. doi: 10.1021/acs.jmedchem.7b00845. Epub 2017 Oct 1.
Fragment-based drug design exploits initial screening of low molecular weight compounds and their concomitant affinity improvement. The multitude of possible chemical modifications highlights the necessity to obtain structural information about the binding mode of a fragment. Herein we describe a novel NMR methodology (LOGSY titration) that allows the determination of binding modes of low affinity binders in the protein-ligand interface and reveals suitable ligand positions for the addition of functional groups that either address or substitute protein-bound water, information of utmost importance for drug design. The particular benefit of the methodology and in contrast to conventional ligand-based methods is the independence of the molecular weight of the protein under study. The validity of the novel approach is demonstrated on two ligands interacting with bromodomain 1 of bromodomain containing protein 4, a prominent cancer target in pharmaceutical industry.
基于片段的药物设计利用低分子量化合物的初步筛选及其伴随的亲和力提高。可能的化学修饰的多样性突出了获得关于片段结合模式的结构信息的必要性。本文描述了一种新的 NMR 方法（LOGSY 滴定），该方法允许确定低亲和力配体在蛋白质-配体界面中的结合模式，并揭示适合添加功能基团的配体位置，这些基团可以解决或替代与蛋白质结合的水，这对于药物设计至关重要。该方法与传统的基于配体的方法相比，特别是其优点在于研究中的蛋白质分子量是独立的。该新方法的有效性在与溴结构域蛋白 4 的溴结构域 1 相互作用的两种配体上得到了证明，溴结构域蛋白 4 是制药行业中一个重要的癌症靶点。
