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Selectivity challenges for aldose reductase inhibitors: A review on comparative SAR and interaction studies.

Authors :
Kumari, Preety
Kohal, Rupali
Bhavana
Gupta, Ghanshyam Das
Verma, Sant Kumar
Source :
Journal of Molecular Structure. Dec2024:Part 1, Vol. 1318, pN.PAG-N.PAG. 1p.
Publication Year :
2024

Abstract

• ALR2, 1st enzyme of polyol pathway, overactives in diabetics, driving complications. • Strategies for managing diabetic complications via ALR2 targeting are exemplified. • Target-level selectivity challenges hindering ALR2 inhibition have been discussed. • Comparative SAR investigations for selectively targeting ALR2 inhibitors over ALR1. • In-depth interaction analysis to illustrate the target selective binding features. Chronic hyperglycemia initiates multiple pathways that contribute to developing complications in individuals with diabetes, ultimately leading to significant health problems and mortality. The extensive research elucidated the pathophysiological role of aldose reductase (ALR2) in the polyol pathway, which significantly contributes to these diabetic complications. ALR2, a rate-limiting enzyme in this pathway, becomes overactive in hyperglycemic conditions and plays a central role in developing diabetic complications. As a result, inhibiting ALR2 has emerged as a promising approach for managing these complications. Despite numerous ALR2 inhibitors, only epalrestat is currently marketed, mainly due to challenges related to their limited selectivity for ALR2 over aldehyde reductase (ALR1). This selectivity issue arises because ALR2 shares 65 % structural similarity with ALR1, leading to concerns about potential toxicity. This article provides a detailed overview of the advancements made in the last decade (2012–2023) in developing ALR2 and ALR1 inhibitors, addressing the selectivity challenges between ALR2 and ALR1 through comparative structure-activity relationship (SAR) analyses. It also explores the intricate interactions of potent ligands within the catalytic sites of both ALR2 and ALR1, offering innovative strategies for designing target-specific ALR2 inhibitors to minimize off-target toxicity. [Display omitted] [ABSTRACT FROM AUTHOR]

Details

Language :
English
ISSN :
00222860
Volume :
1318
Database :
Academic Search Index
Journal :
Journal of Molecular Structure
Publication Type :
Academic Journal
Accession number :
179433530
Full Text :
https://doi.org/10.1016/j.molstruc.2024.139207