Department of Chemistry, Punjabi University, Patiala, Punjab, India.
Molecular Modeling Lab, Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, Punjab, India.
J Mol Model. 2022 Aug 19;28(9):260. doi: 10.1007/s00894-022-05256-y.
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.
科学证据表明，ALR2 调节基因的多态性有利于糖尿病并发症 (DCs) 的易感性。先前的研究已经在 ALR2 调节位点发现了几个单核苷酸多态性 (SNPs)，这些 SNPs 负调节该酶的活性，最终增加了 DCs 的风险。有鉴于此，本研究旨在探讨 ALR2 酶调节位点错义 SNPs 的突变是否也会阻碍 ALR2 抑制剂与 ALR2 结合位点关键氨基酸残基的相互作用。dbSNP 数据库中报道了 ALR2 基因约有 202 个 SNPs。其中，有 18 个 SNPs 负责 ALR2 酶调节位点的点突变，被认为是本研究的对象。然后，使用各种计算工具和网络服务器将这些鉴定的 SNPs 分为稳定或不稳定。进一步使用基于结构的分析方法，研究了 ALR2 的突变构建体对其与知名 ALR2 抑制剂的结合亲和力和结合模式的影响。这项研究确定了三个不稳定的 SNP，即 rs779176563 (C298S)、rs1392886142 (G16A) 和 rs1407261115 (A245T)，这些 SNP 导致对大多数处于临床试验阶段的 ALR2 抑制剂的反应受损。另一方面，携带错义 SNPs rs748119899、rs1402962430 和 rs1467939858 的人群（分别编码 W219S、Q183V 和 S214A）可能会受益于这些 ALR2 抑制剂的治疗。总的来说，该研究的结果表明，ALR2 的抑制剂结合位点的一个 SNP 和辅助因子结合位点的两个 SNP 可能是 ALR2 抑制剂在临床试验中疗效低且不成功的原因。
