Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Research Group in Cheminformatics & Nutrition, Departament de Bioquímica i Biotecnologia, Universitat Rovira i Virgili, Campus de Sescelades, 43007 Tarragona, Spain.
Int J Mol Sci. 2023 Jul 4;24(13):11098. doi: 10.3390/ijms241311098.
Matrix metalloproteinase 13 plays a central role in osteoarthritis (OA), as its overexpression induces an excessive breakdown of collagen that results in an imbalance between collagen synthesis and degradation in the joint, leading to progressive articular cartilage degradation. Therefore, MMP-13 has been proposed as a key therapeutic target for OA. Here we have developed a virtual screening workflow aimed at identifying selective non-zinc-binding MMP-13 inhibitors by targeting the deep S1' pocket of MMP-13. Three ligands were found to inhibit MMP-13 in the µM range, and one of these showed selectivity over other MMPs. A structure-based analysis guided the chemical optimization of the hit compound, leading to the obtaining of a new -acyl hydrazone-based derivative with improved inhibitory activity and selectivity for the target enzyme.
基质金属蛋白酶 13 在骨关节炎（OA）中发挥着核心作用，因为其过表达会导致胶原过度分解，从而导致关节中胶原合成和降解之间失衡，导致进行性关节软骨降解。因此，MMP-13 已被提议作为 OA 的关键治疗靶点。在这里，我们开发了一种虚拟筛选工作流程，旨在通过靶向 MMP-13 的深 S1' 口袋来识别选择性非锌结合 MMP-13 抑制剂。发现有三种配体在微摩尔范围内抑制 MMP-13，其中一种对其他 MMP 具有选择性。基于结构的分析指导了对命中化合物的化学优化，得到了一种新的基于 -酰基腙的衍生物，该衍生物对靶酶具有改善的抑制活性和选择性。
