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

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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.

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The datasets generated during and/or analyzed during the current study have already been provided as a supplementary data.

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Funding

This study was supported by the Indian Council of Medical Research (ICMR), New Delhi, under sanction no ISRM/11(11)/2019.

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Authors and Affiliations

  1. Department of Chemistry, Punjabi University, Patiala, Punjab, India

    Bhawna Vyas & Ashok Kumar Malik

  2. Molecular Modeling Lab, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India

    Shalki Choudhary, Himanshu Verma & Manoj Kumar

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  1. Bhawna Vyas
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  3. Himanshu Verma
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  4. Manoj Kumar
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Contributions

Dr. Bhawna Vyas contributed in conceptualization, material preparation, and data collection and analysis.

Shalki Choudhary contributed in manuscript writing and editing.

Himanshu Verma contributed in some of the in silico part.

Manoj Kumar contributed in some of the in silico part.

Prof. Ashok Kumar Malik contributed in manuscript checking and editing.

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Correspondence to Bhawna Vyas.

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Vyas, B., Choudhary, S., Verma, H. et al. Identification of missense SNP-mediated mutations in the regulatory sites of aldose reductase (ALR2) responsible for treatment failure in diabetic complications. J Mol Model 28, 260 (2022). https://doi.org/10.1007/s00894-022-05256-y

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