Search for non-acidic ALR2 inhibitors: Evaluation of flavones as targeted agents for the management of diabetic complications

Diabetic complications (DC) follow multiple pathophysiological pathways and one of the key pathways is the polyol pathway which involves the metabolism of glucose via aldose reductase (ALR2) and sorbitol dehydrogenase (SDH). ALR2 inhibitors such as epalrestat has already been established as promising candidates for the management of DC. On the basis of pathophysiological understanding of polyol pathway, simultaneous inhibition of ALR2 and SDH may be expected to provide synergistic outcomes in the treatment strategies for DC. Thus, in this study, dual inhibitors of ALR2 and SDH were identified using pharmacophore-based virtual screening. For this purpose, the pharmacophore model for SDH (model ID: AAADH.343) was generated and validated. For screening against ALR2, the pharmacophore model (model ID: AADRR.1109) which was previously reported by our group was applied. Initially, flavones reported by our research group were screened by those two pharmacophore models to obtain hits with an optimum affinity for the catalytic domain of both ALR2 and SDH. Inhibitory potential of identified hits for ALR2 and SDH were then experimentally determined using enzymatic assays reported in the literature. Additional focus was laid on the selectivity of the designed molecules towards ALR2 over ALR1, thus evaluation against ALR1 was also performed. Overall, four molecules FLV-2, FLV-11, FLV-12, and FLV-15 were found to possess significant dual inhibitory activity against ALR2 and SDH, with selectivity over ALR1. Among them, FLV-2 displayed significant dual inhibitory potential with an IC50 value of 0.689 ± 0.018 µM and 0.174 ± 0.003 µM against ALR2 and SDH respectively with a selectivity index of 52.902 to ALR2 over ALR1.