Selectivity determinants of inhibitor binding to the tumour marker human aldose reductase-like protein (AKR1B10) discovered from molecular docking and database screening.

AKR1B10, a human member of the aldo-keto reductase (AKR) superfamily, was recently identified to be linked with several types of cancers, while exhibiting high sequence identity with human aldose reductase (AKR1B1). In order to identify potential inhibitors of AKR1B10, the NCI database which contains approximately 250,000 chemical structures was screened using in silico techniques. Computer aided ligand docking was carried out using the automated Glide program, and potential ligands were selected out based on their chemical complementarity and steric fit within the active site of the enzyme. One of the ligands, 9-methyl-2,3,7-trihydroxy-6-fluorone, showed an IC(50) value of 0.4 microM with a 4-fold selectivity towards AKR1B10 relative to AKR1B1, and its inhibition was competitive with respect to the substrate, showing a K(i) value of 0.2 microM. In addition, through molecular docking in both the AKR1B10-NADP(+) and AKR1B1-NADP(+) complexes, as well as site-directed mutagenesis, non-conserved residues which are involved in inhibitor binding to AKR1B10 were identified and included Lys125 and Gln303. 2010 Elsevier Masson SAS. All rights reserved.