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Amino Acids

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The investigation of structure–activity relationship of polyamine-targeted synthetic compounds from different chemical groups

  • Sergey P. SyatkinEmail author
  • Ekaterina V. Neborak
  • Andrei I. Khlebnikov
  • Marina V. Komarova
  • Natalia A. Shevkun
  • Eduard G. Kravtsov
  • Mikhail L. Blagonravov
  • Enzo Agostinelli
Original Article
  • 25 Downloads
Part of the following topical collections:
  1. Polyamines: Biochemical and Pathophysiological Properties

Abstract

The polyamine (PA) metabolism is involved in cell proliferation and differentiation. Increased cellular PA levels are observed in different types of cancers. Products of PA oxidation induce apoptosis in cancer cells. These observations open a perspective to exploit the enzymes of PA catabolism as a target for anticancer drug design. The substances capable to enhance PA oxidation may become potential anticancer agents. The goal of our study was to explore how the mode of ligand binding with a PA catabolic enzyme is associated with its stimulatory or inhibitory effect upon PA oxidation. Murine N1-acetylpolyamine oxidase (5LFO) crystalline structure was used for molecular docking with ligands of various chemical structures. In vitro experiments were carried out to evaluate the action of the tested compounds upon PA oxidative deamination in a cell-free test system from rat liver. Two amino acid residues (Aps211 and Tyr204) in the structure of 5LFO were found to be significant for binding with the tested compounds. 19 out of 51 screened compounds were activators and 17 were inhibitors of oxidative deamination of PA. Taken together, these results enabled to construct a recognition model with characteristic descriptors depicting activators and inhibitors. The general tendency indicated that a strong interaction with Asp211 or Tyr204 was rather typical for activators. The understanding of how the structure determines the binding mode of compounds with PA catabolic enzyme may help in explanation of their structure–activity relationship and thus promote structure-based drug design.

Keywords

Polyamines Polyamine catabolism Polyamine-targeted agents Molecular docking Structure–activity relationship 

Abbreviations

AA

Amino acid

APAO

N-acetylpolyamine oxidase

BENSpm

Bis(ethyl)norspermine

CPENSpm

N1-cyclopropylmethyl-N1-ethylnorspermine

FAD

Flavine adenine dinucleotide

N1-acetyl-Spm

N1-acetylspermine

PA(s)

Polyamine(s)

PAO

Polyamine oxidase

PDB

Protein Data Bank

SMO

Spermine oxidase

SSAT

Spermine/spermidine-N-acetyltransferase

Spm

Spermine

Spd

Spermidine

MDL 72527

N1,N4-bis(2,3-butadienyl)-1,4-butanediamine dihydrochloride

Notes

Acknowledgements

This work was financially supported by the Ministry of Education and Science of the Russian Federation (the Agreement No 02.A03.21.0008) and by the “RUDN University Program 5-100”. Docking studies were supported by Tomsk Polytechnic University Competitiveness Enhancement Program Grant No. CEP—N. Kizhner Center—213/2018. The authors thank the “International Polyamine Foundation, ONLUS” for the availability to look up in the Polyamines documentation.

Author contributions

All authors listed have contributed to the conception, design, gathering, analysis, or interpretation of data, and have contributed to the writing and intellectual content of the article. All authors gave informed consent to the submission of this manuscript.

Compliance with ethical standards

Conflict of interest

All the authors confirm the permission for this publication and declare no conflict of interests.

Ethics approval and research involving human participants and/or animals

All applicable international, national, and/or institutional guidelines for the care and use of animals were followed. The experiments with the animals were carried out according to the protocols approved by the Ethic Committee of PFUR (protocol no. 17/09-2015). This study does not contain any studies with human participants performed by any of the authors.

Supplementary material

726_2019_2778_MOESM1_ESM.doc (246 kb)
Supplementary material 1 (DOC 246 kb)

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Copyright information

© Springer-Verlag GmbH Austria, part of Springer Nature 2019

Authors and Affiliations

  • Sergey P. Syatkin
    • 1
    Email author
  • Ekaterina V. Neborak
    • 1
  • Andrei I. Khlebnikov
    • 2
    • 3
  • Marina V. Komarova
    • 4
  • Natalia A. Shevkun
    • 5
  • Eduard G. Kravtsov
    • 1
  • Mikhail L. Blagonravov
    • 1
  • Enzo Agostinelli
    • 6
    • 7
  1. 1.Medical InstituteRUDN University (Peoples’ Friendship University of Russia)MoscowRussia
  2. 2.Kizhner Research CenterNational Research Tomsk Polytechnic UniversityTomskRussia
  3. 3.Scientific Research Institute of Biological MedicineAltai State UniversityBarnaulRussia
  4. 4.Samara UniversitySamaraRussia
  5. 5.Drug Product Division, Project Development DepartmentNEARMEDIC PHARMA LLCMoscowRussia
  6. 6.Department of Biochemical SciencesSAPIENZA University of RomeRomeItaly
  7. 7.International Polyamines Foundation, ONLUSRomeItaly

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