In silico study of 4- phosphorylated derivatives of 1,3-oxazole as inhibitors of Candida albicans fructose-1,6- bisphosphate aldolase II

publication · 3 months ago
by Ivan V. Semenyuta, Oleksandr L. Kobzar, Diana M. Hodyna, Volodymyr S. Brovarets, Larysa O. Metelytsia (National Academy of Sciences of Ukraine)
MarvinSketch Instant JChem

In this study, the synthesis, in vitro anti-Candida activity and molecular modeling of 4-phosphorylated derivatives of 1,3-oxazole as inhibitors of Candida albicans fructose-1,6-bisphosphate aldolase (FBA-II) are demonstrated and discussed. Significant similarity of the primary and secondary structure, binding sites and active sites of FBA-II C. albicans and Mycobacterium tuberculosis are established. FBA-II C. albicans inhibitors contained 1,3-oxazole-4-phosphonates moiety are created by analogy to inhibitors FBA-II M. tuberculosis. The experimental studies of the anti-Candida activity of the designed and synthesized compounds have shown their high activity against standard strain and its C.albicans fluconazole resistant clinical isolate. It was hypothesized that the growth suppression of fluconazole-resistant S. albicans strain may be due to the inhibition of aldolase fructose-1,6-bisphosphate. A qualitative homology 3D model of the C. albicans FBA-II was created using SWISS-MODEL server. The probable mechanism of FBA-II inhibition by studied 4-phosphorylated derivatives was shown using molecular docking. The main role of amino acid residues His110, His226, Gly227, Leu248, Val238, Asp144, Lys230, Glu147, Gly227, Ala112, Leu145 and catalytic zinc atom in the formation of stable ligand-protein complexes with DG 1⁄4 e6.89, e7.2, e7.16, e7.5, e8.0, e7.9 kcal/mol was shown. Thus, the positive results obtained in the work were demonstrated the promise of using the proposed homology 3D model of the C. albicans FBA-II as the target for the search and development of new anti-Candida agents against azoleresistant fungal pathogens. Designed and studied 4-phosphorylated derivatives of 1,3-oxazole having a direct inhibiting FBA-II molecular mechanism of action can be used as perspective drug-candidates against resistant C. albicans strains.

Visit the publication