Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Aug 19;28(9):260.
doi: 10.1007/s00894-022-05256-y.

Identification of missense SNP-mediated mutations in the regulatory sites of aldose reductase (ALR2) responsible for treatment failure in diabetic complications

Bhawna Vyas  1 , Shalki Choudhary  2 , Himanshu Verma  2 , Manoj Kumar  2 , Ashok Kumar Malik  3
Affiliations

Identification of missense SNP-mediated mutations in the regulatory sites of aldose reductase (ALR2) responsible for treatment failure in diabetic complications

Bhawna Vyas et al. J Mol Model. .

Abstract

Scientific pieces of evidence indicate that the polymorphism in the ALR2 regulatory gene favors the susceptibility to diabetic complications (DCs). Previous studies have uncovered several single nucleotide polymorphisms (SNPs) in the ALR2 regulatory sites that negatively modulate the activity of this enzyme and eventually increase the risks of DCs. In view of this, the current study aimed at investigating whether the mutation as a resultant of missense SNPs in the regulatory site of ALR2 enzyme can also hamper the interactions of ALR2 inhibitors with the key amino acid residues in the ALR2 binding site. Around 202 SNPs in the ALR2 gene were reported in the dbSNP database. Out of these, eighteen SNPs that are responsible for point mutations in the regulatory sites of ALR2 enzyme were identified and considered for the study. Identified SNPs were then categorized as stabilizing or destabilizing using various in silico tools and webservers. The resulting mutational constructs of ALR2 were further probed for their influence on the binding affinities and binding modes with well-known ALR2 inhibitors using structure-based analyses. This study identified three destabilizing SNPs, i.e., rs779176563 (C298S), rs1392886142 (G16A), and rs1407261115 (A245T), that lead to the compromised response to most of the ALR2 inhibitors which are in clinical trials. On the other hand, treatment with these ALR2 inhibitors may benefit the population which carries missense SNPs rs748119899, rs1402962430, and rs1467939858 that code for W219S, Q183V, and S214A, respectively. Overall findings of the study suggest that one SNP in the inhibitor site and two SNPs in the co-factor site of ALR2 may be responsible for the low efficacy and unsuccessful journey of ALR2 inhibitors in the clinical trials.

Keywords: Aldose reductase; Diabetic complications; Molecular dynamics; SNPs.

PubMed Disclaimer

References

    1. Ruta L, Magliano D, Lemesurier R, Taylor H, Zimmet P, Shaw J (2013) Prevalence of diabetic retinopathy in type 2 diabetes in developing and developed countries. Diabet Med 30:387–398. https://doi.org/10.1111/dme.12119 - DOI - PubMed
    1. Misra A, Gopalan H, Jayawardena R, Hills AP, Soares M, Reza-Albarrán AA et al (2019) Diabetes in developing countries. J diabetes 11:522–39. https://doi.org/10.1111/1753-0407.12913 - DOI - PubMed
    1. Matschinsky FM (2005) Glucokinase, glucose homeostasis, and diabetes mellitus. Curr Diab Rep 5:171–176. https://doi.org/10.1007/s11892-005-0005-4 - DOI - PubMed
    1. Gerich JE (2010) Role of the kidney in normal glucose homeostasis and in the hyperglycaemia of diabetes mellitus: therapeutic implications. Diabet Med 27:136–42. https://doi.org/10.1111/j.1464-5491.2009.02894.x - DOI - PubMed - PMC
    1. Fowler MJ (2008) Microvascular and macrovascular complications of diabetes. Clin diabetes 26:77–82. https://doi.org/10.2337/diaclin.26.2.77 - DOI