Surmiak Ewa, Neochoritis Constantinos G, Musielak Bogdan, Twarda-Clapa Aleksandra, Kurpiewska Katarzyna, Dubin Grzegorz, Camacho Carlos, Holak Tad A, Dömling Alexander
Department of Chemistry, Jagiellonian University, Ingardena 3, 30-060 Krakow, Poland.
Department of Pharmacy, Drug Design Department, University of Groningen, 9713AV Groningen, The Netherlands.
Eur J Med Chem. 2017 Jan 27;126:384-407. doi: 10.1016/j.ejmech.2016.11.029. Epub 2016 Nov 16.
Using the computational pharmacophore-based ANCHOR.QUERY platform a new scaffold was discovered. Potent compounds evolved inhibiting the protein-protein interaction p53-MDM2. An extensive SAR study was performed based on our four-point pharmacophore model, yielding derivatives with affinity to MDM2 in the nanomolar range. Their binding affinity with MDM2 was evaluated using both fluorescence polarization (FP) assay and 2D-NMR-HSQC experiments.
使用基于计算药效团的ANCHOR.QUERY平台发现了一种新的骨架。强效化合物逐渐发展出抑制p53-MDM2蛋白质-蛋白质相互作用的能力。基于我们的四点药效团模型进行了广泛的构效关系研究，得到了对MDM2具有纳摩尔级亲和力的衍生物。使用荧光偏振（FP）测定法和二维核磁共振氢谱（2D-NMR-HSQC）实验评估了它们与MDM2的结合亲和力。
