Novel glyoxalase-I inhibitors possessing a “zinc-binding feature” as potential anticancer agents

Figures & data

Figure 1 Mechanism of MG detoxification utilizing glyoxalase system enzymes.

Abbreviations: MG, methylglyoxal; Glo-I, glyoxalase-1; Glo-II, glyoxalase-2; GSH, Glutathione.

Figure 2 Takasawa perception of the expected pharmacophore and SAR of flavonoids as Glo-I inhibitors.

Abbreviations: SAR, structure–activity relationship; Glo-I, glyoxalase-1; AS, active site.

Figure 3 Active site of the Glo-I enzyme.

Note: The site contains a positively ionized mouth (blue), a hydrophobic pocket (deep: brown), and a zinc atom (gray sphere).
Abbreviation: Glo-I, glyoxalase-1.

Figure 4 Query used for extracting compounds from the Aldrich^CPR database using the Ligand Pharmacophore Mapping protocol.

Table 1 Chemical structures of retrieved hits from Aldrich^CPR, their in vitro enzyme assay results, and corresponding in silico docking scores

No	Compound structure	Inhibition at 50 µM (%)	Inhibition at 25 µM (%)	Flexible docking
1		47.0	34.0	82.45
2		81.1	76.4	83.21
3		68.0	49.1	92.21
4		NA	NA	43.89
5		20.4	NA	52.84
6		4.0	NA	46.65
7		5.55	NA	59.73
Myricetin		99.0	95.0	75.60

Abbreviation: NA, not active.

Figure 5 Docking of compound 2 within the active site of Glo-I.

Notes: The ketol group chelates zinc (gray sphere). The carboxylic acid group forms ionic interactions with the mouth of the active site. para-Chlorophenyl occupies the hydrophobic pocket.
Abbreviation: Glo-I, glyoxalase-1.