1-Deazapurine-Based Alpha-Glucosidase Inhibitors: A Computational Approach for the Treatment of Type 2 Diabetes Mellitus.

IF 3.6 4区医学 Q3 CHEMISTRY, MEDICINAL

Current topics in medicinal chemistry Pub Date : 2026-07-30 DOI:10.2174/0115680266475871260724042822

Faiza Boukli Hacene, Hocine Allali, Sabri Ahmed Cherrak, Wassila Soufi, Said Ghalem, Salim Bouchentouf, Radosław Kowalski

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引用次数: 0

Abstract

Introduction: Optimal therapeutic control of Type 2 Diabetes (T2D) depends on designing Alpha-Glucosidase Inhibitors (AGIs) with high potency. This study employs a rigorous computational approach to evaluate 1-deazapurine-derived ligands, examining their interaction modes and pharmacochemical attributes.

Methods: The methodology involves drug-likeness evaluation, molecular docking, and Molecular Dynamics (MD) simulations to elucidate the thermodynamic stability of the complexes. A key feature is the integration of a detailed Structure-Activity Relationship (SAR) analysis, demonstrating high consistency between computational rankings and established biological inhibitory profiles.

Results: The screening revealed that heteroaromatic rings and bulky aromatic moieties were critical structural determinants for potency. Among the screen compounds, 6-(2-hydroxybenzoyl)-3- (2-phenylethyl)imidazo[4,5-b]pyridine-5-methyl carboxylate (L14), 5-(furan-2-yl)-3-(4- methoxybenzyl)-2-phenyl-7-(trifluoromethyl)imidazo[4,5-b]pyridine (L11), and 3-[2- phenylethyl]-5-thiophene-2-yl-7-(trifluoromethyl)imidazo[4,5-b]pyridine (L4) stood out for their optimal binding affinities. In particular, L11 emerged as the most significant candidate due to its superior interaction energy and structural stability, directly reflecting observed biological trends.

Discussion: These results, supported by favorable ADMET profiles, provide a robust scientific rationale for these ligands as lead compounds for T2D management. While the computational insights are highly consistent with observed trends, further studies will address any potential limitations before progressing.

Conclusion: This study establishes a solid methodological framework for future in vitro and in vivo experimental validation of 1-deazapurine derivatives as potent therapeutic agents.

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1-地氮嘌呤类α -葡萄糖苷酶抑制剂：治疗2型糖尿病的计算方法

2型糖尿病（T2D）的最佳治疗控制取决于设计高效的α -葡萄糖苷酶抑制剂（AGIs）。本研究采用严格的计算方法来评估1-地氮嘌呤衍生的配体，检查它们的相互作用模式和药物化学属性。方法：采用药物相似性评价、分子对接、分子动力学模拟等方法研究配合物的热力学稳定性。一个关键特征是详细的结构-活性关系（SAR）分析的集成，表明计算排名和建立的生物抑制谱之间的高度一致性。结果：筛选结果表明，杂芳烃环和庞大的芳烃部分是药效的关键结构决定因素。在筛选的化合物中，6-（2-羟基苯甲酰）-3-（2-苯乙基）咪唑[4,5-b]吡啶-5-甲基羧酸盐（L14）、5-（呋喃-2-基）-3-（4-甲氧基苄基）-2-苯基-7-（三氟甲基）咪唑[4,5-b]吡啶（L11）和3-[2-苯乙基]-5-噻吩-2-基-7-（三氟甲基）咪唑[4,5-b]吡啶（L4）具有最佳的结合亲和性。特别是L11，由于其优越的相互作用能和结构稳定性，直接反映了观察到的生物学趋势，成为最重要的候选者。讨论：这些结果，由有利的ADMET谱支持，为这些配体作为T2D治疗的先导化合物提供了强有力的科学依据。虽然计算的见解与观察到的趋势高度一致，但在进展之前，进一步的研究将解决任何潜在的局限性。结论：本研究为1-去氮杂嘌呤衍生物作为有效治疗药物的体外和体内实验验证奠定了坚实的方法学框架。

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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来源期刊

Current topics in medicinal chemistry 医学-医药化学

CiteScore

6.40

自引率

2.90%

发文量

186

审稿时长

3-8 weeks

期刊介绍： Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.