Protein Engineering and Biopharmaceutical Sciences Laboratory, Hubei University of Technology, 430068, Wuhan, China.
National Center for Magnetic Resonance in Wuhan, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, Innovation Academy for Precision Measurement Science and Technology, CAS, 33 Hongshanche Road, 430071, Wuhan, Hubei, China.
Nat Commun. 2022 Feb 28;13(1):1087. doi: 10.1038/s41467-022-28721-x.
Overexpressed Mdm2 and its 7homolog MdmX impair p53 activity in many cancers. Small molecules mimicking a p53 peptide can effectively inhibit Mdm2 but not MdmX. Here, we show a strategy for improving lead compounds for Mdm2 and MdmX inhibition based on the multivalency of the p53 peptide. Crystal structures of MdmX complexed with nutlin-3a, a strong Mdm2 inhibitor but a weak one for MdmX, reveal that nutlin-3a fits into the ligand binding pocket of MdmX mimicking the p53 peptide. However, due to distinct flexibility around the MdmX ligand binding pocket, the structures are missing many important intermolecular interactions that exist in the MdmX/p53 peptide and Mdm2/nultin-3a complexes. By targeting these flexible regions, we identify allosteric and additive fragments that enhance the binding affinity of nutlin-3a for MdmX, leading to potent Mdm2/MdmX inhibitors with anticancer activity. Our work provides a practical approach to drug design for signal transduction therapy.
在许多癌症中，过表达的 Mdm2 及其同源物 MdmX 会损害 p53 的活性。模拟 p53 肽的小分子可以有效地抑制 Mdm2，但不能抑制 MdmX。在这里，我们展示了一种基于 p53 肽的多价性来改进 Mdm2 和 MdmX 抑制的先导化合物的策略。与 nutlin-3a （一种强 Mdm2 抑制剂，但对 MdmX 的抑制作用较弱）结合的 MdmX 的晶体结构表明，nutlin-3a 适合于模仿 p53 肽的 MdmX 配体结合口袋。然而，由于 MdmX 配体结合口袋周围的明显灵活性，这些结构缺失了许多存在于 MdmX/p53 肽和 Mdm2/nultin-3a 复合物中的重要分子间相互作用。通过针对这些灵活区域，我们确定了变构和附加片段，增强了 nutlin-3a 与 MdmX 的结合亲和力，从而产生了具有抗癌活性的强效 Mdm2/MdmX 抑制剂。我们的工作为信号转导治疗的药物设计提供了一种实用方法。
