Genome-wide association studies (GWAS) have identified an association between polymorphisms in the FTO gene and obesity. The FTO: rs9939609, an intronic variant, is considered a risk allele for developing diabesity in homozygous and heterozygous forms. This study aimed to investigate the molecular structure of the available inhibitors specific to the FTO mutations along with the rs9939609 variant. We identified the best-suited inhibitor molecules for each mutant type containing the rs9939609 risk allele. Missense mutations unique to obesity and containing the risk allele of rs9939609 were retrieved from dbSNP for this study. Further stability testing for the mutations were carried out using DynaMut and iStable tools. Three mutations (G187A, M223V, and I492V) were highly destabilizing the FTO structure. These three mutants and native FTO were docked with each of the nine-inhibitor molecules collected from literature studies with the help of PyRx and AutoDock. Further structural behavior of the mutants and native FTO were identified with molecular dynamics simulations and MM-PBSA analyses, along with the 19complex inhibitor compound. We found the compound 19complex exhibited better binding interactions and is the top candidate inhibitor for the M223V and I492V mutants. This study provided insights into the structural changes caused due to mutations in FTO, and the binding mechanism of the inhibitor molecules. It could aid in developing antiobesity drugs for treating patients with mutations and risk alleles predisposing to obesity.

中文翻译：

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通过对接和分子动力学策略比较潜在的抑制剂和靶向脂肪量和肥胖相关蛋白导致糖尿病

全基因组关联研究（GWAS）已经确定了FTO基因多态性与肥胖之间的关联。FTO _: rs9939609 是一种内含子变异，被认为是纯合子和杂合子形式的糖尿病风险等位基因。本研究旨在研究 FTO 突变特异性抑制剂的分子结构以及 rs9939609 变体。我们为每种含有 rs9939609 风险等位基因的突变类型确定了最适合的抑制剂分子。本研究从 dbSNP 检索到肥胖特有的错义突变并包含 rs9939609 的风险等位基因。使用 DynaMut 和 iStable 工具对突变进行了进一步的稳定性测试。三个突变（G187A、M223V 和 I492V）使 FTO 结构高度不稳定。在 PyRx 和 AutoDock 的帮助下，这三个突变体和天然 FTO 与从文献研究中收集的九种抑制剂分子中的每一种对接。通过分子动力学模拟和 MM-PBSA 分析以及 19 复合抑制剂化合物，确定了突变体和天然 FTO 的进一步结构行为。我们发现化合物 19complex 表现出更好的结合相互作用，是 M223V 和 I492V 突变体的最佳候选抑制剂。该研究提供了对由 FTO 突变引起的结构变化以及抑制剂分子的结合机制的见解。它可以帮助开发抗肥胖药物，用于治疗具有易患肥胖症的突变和风险等位基因的患者。我们发现化合物 19complex 表现出更好的结合相互作用，是 M223V 和 I492V 突变体的最佳候选抑制剂。该研究提供了对由 FTO 突变引起的结构变化以及抑制剂分子的结合机制的见解。它可以帮助开发抗肥胖药物，用于治疗具有易患肥胖症的突变和风险等位基因的患者。我们发现化合物 19complex 表现出更好的结合相互作用，是 M223V 和 I492V 突变体的最佳候选抑制剂。该研究提供了对由 FTO 突变引起的结构变化以及抑制剂分子的结合机制的见解。它可以帮助开发抗肥胖药物，用于治疗具有易患肥胖症的突变和风险等位基因的患者。