通过临床信息学和分子杂交技术对已上市的临床 DPP-4 抑制剂进行研究,以开发新的 2 型糖尿病药物

IF 2.2 4区 化学 Q2 Engineering Chemical Papers Pub Date : 2024-09-20 DOI:10.1007/s11696-024-03697-8
Lotfi Bourougaa, Mebarka Ouassaf, Bader Y. Alhatlani
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引用次数: 0

摘要

糖尿病通常被称为高血糖症,是目前一种严重的世界性疾病。在临床药理学中,二肽基肽酶 IV(DPP-4)酶对葡萄糖稳态非常重要。临床上,DPP-4 受体阻滞剂是一种重要的口服抗糖尿病药物,可作为二甲双胍之后的替代治疗药物,且无低血糖风险。本研究的目的是通过对 8 种临床许可的 DPP-4 抑制剂进行分子杂交,创造出新型、强效的 DPP-4 抑制剂。分子杂交过程产生了五种新型杂交 DPP-4 抑制剂,初步计算研究表明,与已获批准的 DPP-4 抑制剂相比,这些抑制剂可能会表现出更好的选择性。利用利宾斯基五则和其他药物相似性过滤器评估了杂交抑制剂的药代动力学特征,包括它们的溶解度和通过生物组织的潜力,结果表明这些抑制剂具有到达 DPP-4 活性位点的有利特性。此外,还使用基本毒性过滤器和 PASS 对建议的抑制剂的可能毒性进行了调查,结果表明这些抑制剂在潜在毒性和新陈代谢方面没有立即出现问题。此外,还通过机器学习和人工智能算法开发了合成建议化合物的机制。在生物分子层面,使用 Gromacs 软件包对所有研究系统进行了分子动力学模拟(100 ns)。通过动态交叉相关矩阵、自由能景观和 MM-PBSA 计算,分析了分子动力学轨迹并评估了 DPP-4 与所设计化合物发生分子相互作用后的动态位移,所有数据都表明,与临床 DPP-4 抑制剂(阿格列汀)相比,所提出的 DPP-4 抑制剂能产生极其稳定的复合物。最后,本研究的发现可能会极大地促进新型强效 DPP-4 抑制剂的开发,并有助于寻找治疗 2 型糖尿病的新药物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

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Clinical informatics and molecular hybridization of established clinical DPP-4 inhibitors to generate next-level diabetes type 2 drugs

Diabetes mellitus, often known as hyperglycemia, is a serious worldwide disease now. In clinical pharmacology, the dipeptidyl peptidase IV (DPP-4) enzyme is important for glucose homeostasis. The clinical DPP-4 blockers are essential oral antidiabetic medications used as alternate treatment following metformin inability as insulinotropic drugs with no inherent risk of hypoglycemia. The objective of this study is to create novel and potent DPP-4 inhibitors by molecular hybridization of eight clinically licensed DPP-4 inhibitors. Molecular hybridization process led to the creation of five novel hybridized DPP-4 inhibitors, which preliminary computational studies suggest may exhibit improved selectivity compared to authorized DPP-4 inhibitors. The pharmacokinetic features of the hybridized inhibitors, including their solubility and potential to pass through biological tissues, were evaluated using Lipinski’s rule of five and other druglikeness filters, indicating favorable properties for reaching the DPP-4 active site. Furthermore, the possible toxicity of suggested inhibitors was investigated using basic toxicity filters and PASS, indicating no immediate red flags regarding their potential toxicity and metabolism. In addition, a mechanism for synthesizing the proposed compounds has been developed via machine learning and artificial intelligence algorithms. At the biomolecular level, using the Gromacs package, molecular dynamics simulations (100 ns) were performed for all the studied systems. Following analyzing the molecular dynamics trajectories and evaluating the dynamic shifts of DPP-4 after its molecular interactions with the designed compounds via dynamic cross-correlation matrix, free energy landscape and MM-PBSA calculations, all data show that the proposed DPP-4 inhibitors create extremely stable complexes when compared to the clinical DPP-4 inhibitor (alogliptin). Finally, the findings of this study might greatly contribute to the development of novel and potent DPP-4 inhibitors and assist in the search for new medications for diabetes type 2.

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来源期刊
Chemical Papers
Chemical Papers Chemical Engineering-General Chemical Engineering
CiteScore
3.30
自引率
4.50%
发文量
590
期刊介绍: Chemical Papers is a peer-reviewed, international journal devoted to basic and applied chemical research. It has a broad scope covering the chemical sciences, but favors interdisciplinary research and studies that bring chemistry together with other disciplines.
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