Leveraging the multivalent p53 peptide-MdmX interaction to guide the improvement of small molecule inhibitors

Xiyao Cheng, Rong Chen, Ting Zhou, Bailing Zhang, Zichun Li, Meng Gao, Yongqi Huang (), Huili Liu () and Zhengding Su ()
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Xiyao Cheng: Hubei University of Technology
Rong Chen: Hubei University of Technology
Ting Zhou: Hubei University of Technology
Bailing Zhang: Hubei University of Technology
Zichun Li: Hubei University of Technology
Meng Gao: Hubei University of Technology
Yongqi Huang: Hubei University of Technology
Huili Liu: Innovation Academy for Precision Measurement Science and Technology
Zhengding Su: Hubei University of Technology

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract 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.

Date: 2022
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DOI: 10.1038/s41467-022-28721-x

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