The virtual screening for potential allosteric inhibitors targeting PIF-pocket of MAST protein kinases

  • A. O. Steshenko Institute of Food Biotechnology and Genomics NAS of Ukraine, Ukraine, 04123, Kyiv, Baidy Vyshnevetskoho str., 2A; Educational and Scientific Center "Institute of Biology and Medicine" of Taras Shevchenko National University of Kyiv, Ukraine, 01601, Kyiv, Volodymyrska str., 64/13 https://orcid.org/0009-0008-2503-5206
  • S. P. Ozheredov Institute of Food Biotechnology and Genomics, Natl. Acad. Sci. Ukraine, Ukraine, 04123, Kyiv, Baidy-Vyshnevetskoho str., 2А https://orcid.org/0000-0003-4710-0706
  • S. I. Spivak Institute of Food Biotechnology and Genomics, Natl. Acad. Sci. Ukraine, Ukraine, 04123, Kyiv, Baidy-Vyshnevetskoho str., 2А https://orcid.org/0000-0002-1928-2744
  • Ya. B. Blume Institute of Food Biotechnology and Genomics, Natl. Acad. Sci. Ukraine, Ukraine, 04123, Kyiv, Baidy-Vyshnevetskoho str., 2А; Educational and Scientific Center "Institute of Biology and Medicine" of Taras Shevchenko National University of Kyiv, Ukraine, 01601, Kyiv, Volodymyrska str., 64/13 https://orcid.org/0000-0001-7078-7548
  • P. A. Karpov Institute of Food Biotechnology and Genomics, Natl. Acad. Sci. Ukraine, Ukraine, 04123, Kyiv, Baidy-Vyshnevetskoho str., 2А https://orcid.org/0000-0002-6876-642X
DOI: https://doi.org/10.7124/FEEO.v36.1728
Keywords: MAST family, protein kinases, inhibitors, ligands, binding site

Abstract

Aim. The objective of current study was the virtual screening for potential allosteric inhibitors of MAST protein kinases, as well as revision of their isotype-specific potential. Methods. Literature and database search. Molecular modeling, pharmacophore screening, artificial intelligence, molecular docking, etc. Results. Based on pharmacophore screening of Enamine Ltd chemical space, 23 potential effectors of the PIF site of MAST protein kinases were selected. Based on AI reconstruction of protein-ligand complexes, the ATP-, PIF- and K-sites of MAST protein kinases where predict for potential binding of selected compounds. Subsequent CCDC GOLD molecular docking, identify the PIF-pocket as the priory site for selected compounds binding, and the leaders of screening where selected. Conclusions. Based on the complex protocol of Enamine Ltd. (4,117,328 compounds/60,516,302 conformers) chemical space virtual screening, 23 perspective PIF-site specific inhibitors of MAST protein kinases were selected. The possibility of isotype-specific inhibition of representatives of the MAST family was revealed. The leading compounds were selected for further combinatorial design and laboratory testing.

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