Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Bioinformatics Research Center, School of Pharmacy and Pharmaceutical Sciences, Isfahan University of Medical Sciences, Isfahan 81746-73461, Iran.
Int J Mol Sci. 2023 Apr 20;24(8):7578. doi: 10.3390/ijms24087578.
In this paper, we present the development of a computer-based repurposing approach to identify FDA-approved drugs that are potentially able to interfere with irisin dimerization. It has been established that altered levels of irisin dimers are a pure hallmark of lipodystrophy (LD) syndromes. Accordingly, the identification of compounds capable of slowing down or precluding the irisin dimers' formation could represent a valuable therapeutic strategy in LD. Combining several computational techniques, we identified five FDA-approved drugs with satisfactory computational scores (iohexol, XP score = -7.70 kcal/mol, SP score = -5.5 kcal/mol, ΔG = -61.47 kcal/mol, ΔG (average) = -60.71 kcal/mol; paromomycin, XP score = -7.23 kcal/mol, SP score = -6.18 kcal/mol, ΔG = -50.14 kcal/mol, ΔG (average) = -49.13 kcal/mol; zoledronate, XP score = -6.33 kcal/mol, SP score = -5.53 kcal/mol, ΔG = -32.38 kcal/mol, ΔG (average) = -29.42 kcal/mol; setmelanotide, XP score = -6.10 kcal/mol, SP score = -7.24 kcal/mol, ΔG = -56.87 kcal/mol, ΔG (average) = -62.41 kcal/mol; and theophylline, XP score = -5.17 kcal/mol, SP score = -5.55 kcal/mol, ΔG = -33.25 kcal/mol, ΔG (average) = -35.29 kcal/mol) that are potentially able to disrupt the dimerization of irisin. For this reason, they deserve further investigation to characterize them as irisin disruptors. Remarkably, the identification of drugs targeting this process can offer novel therapeutic opportunities for the treatment of LD. Furthermore, the identified drugs could provide a starting point for a repositioning approach, synthesizing novel analogs with improved efficacy and selectivity against the irisin dimerization process.
本文提出了一种基于计算机的重新利用方法，旨在鉴定潜在能够干扰鸢尾素二聚体形成的已获 FDA 批准的药物。已经确定，鸢尾素二聚体水平的改变是脂肪营养不良 (LD) 综合征的一个明确标志。因此，鉴定能够减缓或阻止鸢尾素二聚体形成的化合物可能是 LD 治疗的一种有价值的策略。我们结合了几种计算技术，鉴定了五种具有令人满意的计算评分的已获 FDA 批准的药物（碘海醇，XP 评分 = -7.70 千卡/摩尔，SP 评分 = -5.5 千卡/摩尔，ΔG = -61.47 千卡/摩尔，ΔG（平均）= -60.71 千卡/摩尔；巴龙霉素，XP 评分 = -7.23 千卡/摩尔，SP 评分 = -6.18 千卡/摩尔，ΔG = -50.14 千卡/摩尔，ΔG（平均）= -49.13 千卡/摩尔；唑来膦酸，XP 评分 = -6.33 千卡/摩尔，SP 评分 = -5.53 千卡/摩尔，ΔG = -32.38 千卡/摩尔，ΔG（平均）= -29.42 千卡/摩尔；塞美拉肽，XP 评分 = -6.10 千卡/摩尔，SP 评分 = -7.24 千卡/摩尔，ΔG = -56.87 千卡/摩尔，ΔG（平均）= -62.41 千卡/摩尔；和茶碱，XP 评分 = -5.17 千卡/摩尔，SP 评分 = -5.55 千卡/摩尔，ΔG = -33.25 千卡/摩尔，ΔG（平均）= -35.29 千卡/摩尔），这些药物可能能够破坏鸢尾素的二聚化。因此，它们值得进一步研究，以将其鉴定为鸢尾素破坏剂。值得注意的是，鉴定针对这一过程的药物可以为 LD 的治疗提供新的治疗机会。此外，鉴定出的药物可以为重新定位方法提供一个起点，合成具有改善的疗效和对鸢尾素二聚化过程的选择性的新型类似物。
