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3D-QSAR, molecular docking and in silico ADMET studies of propiophenone derivatives with anti-HIV-1 protease activity

Abstract

HIV protease inhibitors are one of the most important agents for the treatment of HIV infection. In this work, molecular modeling studies combining 3D-QSAR, molecular docking, MESP, HOMO, and LUMO energy calculations were performed on propiophenone derivatives to explore structure activity relationships and structural requirements for the inhibitory activity. The aim of this study was to create a field point–based 3D-QSAR (3D-Quantitative structure-activity relationship) model by using chalcone structures with anti-HIV-1 protease activity from our previous study and to design new potentially more potent and safer inhibitors. The developed model showed acceptable predictive and descriptive capability as represented by standard statistical parameters R2 (0.94) and Q2 (0.59). High correlation between experimental and predicted activities of training set is noticed. All compounds fit into the defined applicability domain. The derived pharmacophoric features were further supported by MESP and Mulliken charge analysis using density functional theory. Statistically significant variables from 3D-QSAR were used to define key structural characteristics which enhance anti-HIV-1 protease activity. This information has been used to design new structures with anti-HIV-1 protease activity. Docking studies were conducted to understand the interactions in predicted compounds. All the compounds were subjected to in silico ADMET profiling in order to select the best potential drug candidates.

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Availability of data and material

The data that supports the findings of this study are available within the article.

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Acknowledgements

We thank the COST Action CA17120 Chemobrionics (CBrio) of the European Community for support.

Funding

This research was funded by the Ministry of Education, Science and Technological Development of the Republic of Serbia grant number 451-03-9/2021-14/200026. S.G. received support from the Serbian Ministry of Education and Science (Grant No. 451-03-9/2021-14/200026).

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Authors and Affiliations

Authors

Contributions

M.J., K.N., and N.T. contributed toward the 3DQSAR and ADMET analysis, as well as the interpretation of the relevant results. M.J. contributed also to the docking studies. S.G. performed the DFT calculations, contributed to the docking studies, and interpreted the results. S.G., B.I., and Z.V. coordinated the research and wrote the final manuscript based on the research reports. All the authors exchanged opinions concerning the progress of the project and commented on the preparation of the manuscript at all stages. All the authors have read and agreed to the final version of the manuscript.

Corresponding authors

Correspondence to Milan Jovanović, Branka Ivković or Sonja Grubišić.

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The authors declare no competing interests.

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Jovanović, M., Turković, N., Ivković, B. et al. 3D-QSAR, molecular docking and in silico ADMET studies of propiophenone derivatives with anti-HIV-1 protease activity. Struct Chem 32, 2341–2353 (2021). https://doi.org/10.1007/s11224-021-01810-1

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  • DOI: https://doi.org/10.1007/s11224-021-01810-1

Keywords

  • Quantitative structure–activity relationship(s) (QSAR)
  • Computer-aided drug design
  • HIV/AIDS
  • Protease(s)
  • HOMO-LUMO
  • Computational ADME
  • Molecular docking