Discovery of New Selective Human Aldose Reductase
Inhibitors through Virtual Screening Multiple Binding Pocket Conformations
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Abstract
Aldose
reductase reduces glucose to sorbitol. It plays a key role in many
of the complications arising from diabetes. Thus, aldose reductase
inhibitors (ARI) have been identified as promising therapeutic agents
for treating such complications of diabetes, as neuropathy, nephropathy,
retinopathy, and cataracts. In this paper, a virtual screening protocol
applied to a library of compounds in house has been utilized to discover
novel ARIs. IC<sub>50</sub>’s were determined for 15 hits that
inhibited ALR2 to greater than 50% at 50 μM, and ten of these
have an IC<sub>50</sub> of 10 μM or less, corresponding to a
rather substantial hit rate of 14% at this level. The specificity
of these compounds relative to their cross-reactivity with human ALR1
was also assessed by inhibition assays. This resulted in identification
of novel inhibitors with IC<sub>50</sub>’s comparable to the
commercially available drug, epalrestat, and greater than an order
of magnitude better selectivity