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Ukr. Bioorg. Acta 2021, Vol. 16, N1, 25-33.

In vitro and in silico study of 1,3-oxazol-4-yltriphenylphosphonium salts as potential inhibitors of Candida albicans transglycosylase

Ivan V. Semenyuta*, Maria M. Trush, Diana M. Hodyna, Maryna V. Kachaeva,
Larysa O. Metelytsia, Volodymyr S. Brovarets

V. P. Kukhar Institute of Bioorganic Chemistry and Petrochemistry of the NAS of Ukraine, 1 Murmanska St., Kyiv, 02094, Ukraine
tel.: +380-44-573-2595; e-mail: ivan@bpci.kiev.ua

The previously established in vitro high antimicrobial potential of triphenylphosphonium salts (TPPs) against bacterial (Staphylococcus aureus ATCC 25923 and multi-drug resistant (MDR)) and fungal (Candida albicans ATCC 10231 and MDR) strains made it possible to propose a molecular mechanism of action of these compounds associated with transglycosylase (TG) activity. The hypothesis was based on the well-known literature data on TPPs as inhibitors of S. aureus TG. The created homology model of TG C. albicans is optimal in terms of such quality indicators as GMQE (0.61), ERRAT (overall quality factor 95.904) and Ramachandran plot analysis (90% amino acid residues in the favored regions). Molecular docking of the most active ligands 1a-d, 3c into the active center of the created homology C. albicans TG model demonstrated the formation of stable ligand-protein complexes with binding energies in the range from -8.9 to -9.7 kcal/mol due to the various types of interactions. An important role in complex formation belongs to amino acid residues TYR307, TYR107, GLU275, ALA108 and PRO136. The presented qualitative homologous model of C. albicans TG can be used to search and create new agents with a dual mechanism of antimicrobial action. 1,3-oxazol-4-yltriphenylphosphonium salts 1a-d, 3c perform the perspective objects for further study as antimicrobials against infectious MDR pathogens.

transglycosylase; triphenylphosphonium salts; 1,3-oxazole; Candida albicans; Staphylococcus aureus.

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