Center of Organic and Medicinal Chemistry, Institute of Chemistry, and Biotechnology, Zurich University of Applied Sciences (ZHAW), Einsiedlerstrasse 31, 8820, Wädenswil, Switzerland.
Chemistry. 2019 Jun 18;25(34):7960-7980. doi: 10.1002/chem.201805361. Epub 2019 May 2.
Matrix metalloproteinases (MMPs) are involved in a multitude of severe diseases. Despite MMPs being considered druggable targets, past drug-discovery programs have not delivered the anticipated clinical benefits. This review examines the latest structural evolution of small-molecule inhibitors of MMPs, with a focus on the development of novel chemical entities with improved affinity and selectivity profiles. X-ray crystallographic data of the protein targets and cocrystal structures with inhibitors proved to be key for the success achieved during this ambitious endeavor. An evolutionary view on the structural diversity generated for this class of molecules is provided. This encouraging development paves the way for the clinical utilization of this class of highly relevant therapeutic targets. The structure-based design of superior MMP inhibitors highlights the power of this technique and displays strategies for the development of treatment options based on the modulation of challenging drug targets.
基质金属蛋白酶（MMPs）参与了多种严重疾病。尽管 MMP 被认为是可成药的靶点，但过去的药物发现计划并没有带来预期的临床获益。本综述考察了 MMP 小分子抑制剂的最新结构演变，重点是开发具有改善亲和力和选择性特征的新型化学实体。蛋白质靶标的 X 射线晶体学数据和与抑制剂的共晶结构被证明是在这一雄心勃勃的努力中取得成功的关键。为这一类分子提供了关于结构多样性的进化观点。这一令人鼓舞的发展为这一类高度相关的治疗靶点的临床应用铺平了道路。基于结构的高级 MMP 抑制剂设计突出了该技术的强大功能，并展示了基于调节具有挑战性的药物靶点的治疗选择的发展策略。
