Pursuing aldose reductase inhibitors through in situ cross-docking and similarity-based virtual screening.
Aldose reductase (ALR2) is a critical enzyme in the development of the major complications of diabetes mellitus. Herein, new molecular entities active against ALR2 were discovered through an integrated receptor- and ligand-based virtual screening campaign. Twelve candidates were found to inhibit this enzyme in the micromolar range including two ligands having an IC(50) below 3 muM. Six new compounds, structurally unrelated to the known ARIs, have been identified, opening up opportunity for lead optimization.
Cosconati
Sandro
S
Dipartimento di Chimica Farmaceutica e Tossicologica, Universita di Napoli "Federico II", Via D. Montesano 49, 80131 Napoli, Italy.
Marinelli
Luciana
L
La Motta
Concettina
C
Sartini
Stefania
S
Da Settimo
Federico
F
Olson
Arthur J
AJ
Novellino
Ettore
E
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D014584:User-Computer Interface
D004791:Enzyme Inhibitors; D008024:Ligands; D000449:Aldehyde Reductase