A Novel Combined Pharmacophore Mapping and Quantitative Structure Selectivity Relationship Analysis for the Development of Potent and Selective Human Aldose Reductase Inhibitors
Present study describes the use of multiple pharmacophore mapping and three dimensional quantitative
structure selectivity relationship (3D-QSSR) analysis for human aldose reductase (hALR2) and human aldehyde reductase
(hALR1) inhibitors to develop selective molecules against hALR2. Two pharmacophore models one each for highly
active hALR2 inhibitors and highly active hALR1 inhibitors were generated. Atom based 3D-QSSR analysis was
performed employing docking based alignment of molecules. Sequential multi-step virtual screening was performed to
screen PHASE database of approximately 1.5 million molecules. Finally, 22 potent and highly selective hALR2 inhibitors
were obtained as potential hits using virtual screening protocol. This study of multiple pharmacophore mapping combined
with 3D-QSSR analysis provided deep insight into the structural features requirement for selectivity and may be used as
novel tool to design new selective and potent hALR2 inhibitors.
Keywords: PHASE, hALR2, hALR1, diabetic complications, polyol pathway.
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