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Simulation of MDM2 N-terminal domain conformational lability in the presence of imidazoline based inhibitors of MDM2-p53 protein–protein interaction

  • Maxim Gureev
  • Daria Novikova
  • Tatyana Grigoreva
  • Svetlana Vorona
  • Alexander Garabadzhiu
  • Vyacheslav TribulovichEmail author
Article
  • 35 Downloads

Abstract

Targeting of MDM2-p53 protein–protein interaction is a current approach for the development of potent anticancer agents. The classical pharmacophore hypothesis for the design of such molecules describes the three point binding of a small molecule inhibitor to the MDM2 protein. However, this hypothesis is not confirmed when considering the activity of a number of known potent MDM2 inhibitors. Here we demonstrate the important role of the flexible N-terminal region of the MDM2 protein in the binding with small molecule compounds, which contributes to the transition from three point binding to four point binding during the development of new anticancer agents. To evaluate the contribution of the MDM2 N-terminal region to the structure–activity relationship of known MDM2 inhibitors, compounds of nutlin series, whose spatial configuration was shown to dramatically affect the target activity, were used as objects of the study. The key amino acid residues within the N-terminal region involved in the interaction with small molecule ligands were determined by means of molecular dynamics. The conformational stability of the flexible MDM2 fragment was simulated under different conditions. The effects of point mutations on the N-terminal region stability were also demonstrated.

Keywords

MDM2 Conformational dynamics MDM2 N-terminal domain Molecular dynamics simulation Enantiomeric inhibitors 

Notes

Acknowledgements

This work was financially supported by the Russian Science Foundation (Project No. 16-13-10358).

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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Laboratory of Molecular PharmacologySaint Petersburg State Institute of TechnologySaint PetersburgRussia

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