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Journal of Molecular Modeling

, 24:337 | Cite as

In silico assessment of new progesterone receptor inhibitors using molecular dynamics: a new insight into breast cancer treatment

  • Vahid Zarezade
  • Marzie Abolghasemi
  • Fakher Rahim
  • Ali Veisi
  • Mohammad Behbahani
Original Paper

Abstract

Nowadays, breast cancer is one of the most widespread malignancies in women, and the second leading cause of cancer death among women. The progesterone receptor (PR) is one of the treatment targets in breast cancer, and can be blocked with selective progesterone receptor modulators (SPRMs). Since administration of chemical drugs can cause serious side effects, and patients, especially those undergoing long-term treatment, can suffer harmful consequences, there is an urgent need to discover novel potent drugs. Large-scale structural diversity is a feature of natural compounds. Accordingly, in the present study, we selected a library of 20,000 natural compounds from the ZINC database, and screened them against the PR for binding affinity and efficacy. In addition, we evaluated the pharmacodynamics and ADMET properties of the compounds and performed molecular docking. Moreover, molecular dynamics (MD) simulation was carried out in order to examine the stability of the protein. In addition, principal component analysis (PCA) was performed to study the motions of the protein. Finally, the MMPBSA method was applied in order to estimate the binding free energy. Our docking results reveal that compounds ZINC00936598, ZINC00869973 and ZINC01020370 have the highest binding energy into the PR binding site, comparable with that of Levonorgestrel (positive control). Moreover, RMSD, RMSF, Rg and H-bond analysis demonstrate that the lead compounds preserve stability in complex with PR during simulation. Our PCA analysis results were in accordance with MD results and the binding free energies support the docking results. This study paves the way for discovery of novel drugs from natural sources and with optimal efficacy, targeting the PR.

Graphical Abstract

The binding mode of new progesterone receptor inhibitors.

Keywords

Molecular dynamics simulation Docking Progesterone receptor Inhibitor Breast cancer Virtual screening 

Notes

Acknowledgment

We thank Behbahan Faculty of Medical Sciences for financial support (grant number: 9523).

Compliance with ethical standards

Conflict of interest

None Declared.

Supplementary material

894_2018_3858_MOESM1_ESM.pdf (5.6 mb)
ESM 1 (PDF 5746 kb)

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Behbahan Faculty of Medical SciencesBehbahanIran
  2. 2.Genetic Division, Department of Biology, Faculty of Basic ScienceShahrekord UniversityShahrekordIran
  3. 3.Thalassemia and Hemoglobinopathy Research Centre, Health Research InstituteAhvaz Jundishapur University of Medical SciencesAhvazIran
  4. 4.Faculty of EngineeringShohadaye Hoveizeh University of TechnologySusangerdIran

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