Fig 1.
ALR2 mediated Polyol pathway.
Fig 2.
ARIs of synthetic (1–5) and natural origin (6) developed during last few decades.
Fig 3.
Tautomeric forms of curcumin.
Fig 4.
Chemical structure of curcuminoids (compound 1–3), synthetic curcumin analogues (compound 4–21) along with their observed ALR2 inhibitory activity (IC50), pIC50, predicted pIC50, residual activity, and drug likeness/ADME screening Data.
TTest set compounds; molecule violating drug-likeness/ADME screening due to: *molecular weight > 500, and #Log P > 5.
Fig 5.
Predicted binding cavities (1–5) (green) within ALR2 (secondary structure).
Fig 6.
Cavity 1 (green) with co-crystalized epalrestat (red) and its corresponding amino acid residues.
Fig 7.
Projected binding pockets in the active site of ALR2 according to previously performed X-ray crystallography and mutagenesis studies [55–59].
Table 1.
Major cavities (1–5) detected in ALR2 along with their volume, surface area, and position.
Fig 8.
Docking view of compound 9 (Mol. Wt. 324.33) into cavity 1 (green) of ALR2 with its constituting amino acid residues.
Table 2.
MolDock, Re-rank and H-Bond scores of compound 9, Quercetin and Epalrestat.
Fig 9.
Steric interactions (Id. 1–5, red dashed bonds) of compound 9 with ALR2.
Table 3.
Description of steric interactions shown by compound 9 with ALR2.
Fig 10.
Hydrogen bond interactions (H-bond Id. 1–5, green dashed bonds) of compound 9 with ALR2.
Table 4.
Description of H-bond interactions shown by compound 9 with ALR2.
Table 5.
Statistical quality of 3D-QSAR models generated at 0.5 Å and 1.0 Å grid resolutions using PLS regression with different alignment approaches.
Fig 11.
Electrostatic master grid maps at 0.5 Å (A) and 1.0 Å (B) grid resolutions.
Fig 12.
Steric master grid maps at 0.5 Å (A) and 1.0 Å (B) grid resolutions.
Fig 13.
Pharmacophoric frameworks or spatial fingerprints (A and B) of curcumin analogues having favourable interactions with ALR2.
