Structure-Based Rational Design of Novel Inhibitors Against Fructose-1,6-Bisphosphate Aldolase fromCandida albicans

Abstract

Class II fructose-1,6-bisphosphate aldolases (FBA-II) are attractive new targets for the discovery of drugs to combat invasive fungal infection, because they are absent in animals and higher plants. Although several FBA-II inhibitors have been reported, none of these inhibitors exhibit antifungal effect so far. In this study, several novel inhibitors of FBA-II from C. albicans (Ca-FBA-II) with potent antifungal effects were rationally designed by jointly using a specific protocols of molecular docking-based virtual screening, accurate binding-conformation evaluation strategy, synthesis and enzymatic assays. The enzymatic assays reveal that the compounds 3c, 3e-g, 3j and 3k exhibit high inhibitory activity against Ca-FBA-II (IC < 10 μM), and the most potential inhibitor is 3g, with IC value of 2.7 μM. Importantly, the compounds 3f, 3g, and 3l possess not only high inhibitions against Ca-FBA-II, but also moderate antifungal activities against C. glabrata (MIC = 4-64 μg/mL). The compounds 3g, 3l, and 3k in combination with fluconazole (8 μg/mL) displayed significantly synergistic antifungal activities (MIC < 0.0625 μg/mL) against resistant Candida strains, which are resistant to azoles drugs. The probable binding modes between 3g and the active site of Ca-FBA-II have been proposed by using the DOX (docking, ONIOM, and XO) strategy. To our knowledge, no FBA-II inhibitors with antifungal activities against wild type and resistant strains from Candida were reported previously. The positive results suggest that the strategy adopted in this study are a promising method for the discovery of novel drugs against azole-resistant fungal pathogens in the future.

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

“…Our assumption about the phosphonates contained inhibitors of FBA-II C. albicans is confirmed by the existence of FBP, DHAP and PGH analogues with high inhibitory activity to this enzyme [33]. It should also be noted that one of the most studied FBA-II is the FBA-II M. tuberculosis [34].…”

“…1) confirm the significant similarity of protein structures of enzymes, analogically to Han X. et al. [33]. To search of the enzyme inhibitors optimal binding center, a number of FBA-II M. tuberculosis crystallographic structure [34, 39] were used.…”

Targeting Metalloenzymes for Therapeutic Intervention

“…This includes the use of MBPs such as dipicolinic acid, 1109 8-hydroxyquinoline, 1098 and hydrazine (FBAi-3, FBAi-4, FBAi-5, FBAi-6, Figure 113). 1114 2-Carboxy-8-hydroxyquinoline is a non-completive inhibitor (FBAi-4, IC 50 = 10 μM) against MtFBA and showed effectively no inhibition against class I FBA. 1098 X-ray crystallography, biochemical, and biophysical studies show FBAi-4 binds in a tridentate manner to the active site Zn 2+ ion and displaces ligating residue His212, resulting in a trigonal bipyramid coordination geometry (Figure 114).…”

“…Various phenylhydrazone derivatives were developed from this hit, with the most potent inhibitor FBAi-6 achieving an IC 50 value of 2.7 μM against CaFBA. Through computational docking, the hydrazone nitrogen atom is predicted to coordinate to the Zn 2+ ion in monodentate fashion, resulting in a tetrahedral coordination geometry; 1114 however, there is no experimental evidence to verify this mode of binding. Phenylhydrazone inhibitors exhibited moderate antifungal activities against C. glabrata and synergistic antifungal activities in combination antifungal drug fluconazole.…”

Structure-based identification of a potential non-catalytic binding site for rational drug design in the fructose 1,6-biphosphate aldolase from Giardia lamblia

“…In infective diseases, rational drug design involves the selection of an essential biological target and the search for a molecule that can interfere with its biological function, thus decreasing the viability of the pathogen. In this respect, the glycolytic enzyme FBPA has been largely proposed as pharmacological target against bacteria 36–43 , fungus 44,45 and protozoan 46–50 , including G . lamblia 15,19,20 .…”