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

Autor: Cheng X; Protein Engineering and Biopharmaceutical Sciences Laboratory, Hubei University of Technology, 430068, Wuhan, China., Chen R; Protein Engineering and Biopharmaceutical Sciences Laboratory, Hubei University of Technology, 430068, Wuhan, China., Zhou T; Protein Engineering and Biopharmaceutical Sciences Laboratory, Hubei University of Technology, 430068, Wuhan, China., Zhang B; Protein Engineering and Biopharmaceutical Sciences Laboratory, Hubei University of Technology, 430068, Wuhan, China., Li Z; Protein Engineering and Biopharmaceutical Sciences Laboratory, Hubei University of Technology, 430068, Wuhan, China., Gao M; Protein Engineering and Biopharmaceutical Sciences Laboratory, Hubei University of Technology, 430068, Wuhan, China., Huang Y; Protein Engineering and Biopharmaceutical Sciences Laboratory, Hubei University of Technology, 430068, Wuhan, China. yqhuang@hbut.edu.cn., Liu H; 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. liuhuili@wipm.ac.cn., Su Z; Protein Engineering and Biopharmaceutical Sciences Laboratory, Hubei University of Technology, 430068, Wuhan, China. zhengdingsu@hbut.edu.cn.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2022 Feb 28; Vol. 13 (1), pp. 1087. Date of Electronic Publication: 2022 Feb 28.
DOI: 10.1038/s41467-022-28721-x
Abstrakt: 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.
(© 2022. The Author(s).)
Databáze: MEDLINE
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