海洋天然产物作为2型糖尿病葡萄糖激酶激活剂的结构引导发现：计算视角。

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling Pub Date : 2025-09-29 DOI:10.1016/j.jmgm.2025.109181

Heyram Krishnakumar , Manikandan Jayaraman , Dhamodharan Prabhu , Jeyaraman Jeyakanthan

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引用次数: 0

摘要

糖尿病是一种普遍的代谢紊乱，是全球第九大死亡原因。尽管已有有效的降糖药，但仍迫切需要更有效、副作用最小的治疗方法。针对关键的代谢调节因子，如酶、转运体和受体，为药物发现提供了有希望的途径。葡萄糖激酶（GCK）是葡萄糖代谢中的关键酶，它催化葡萄糖转化为葡萄糖-6-磷酸，并具有葡萄糖传感器的功能，使其成为2型糖尿病（T2DM）的一个非常有吸引力的治疗靶点。本研究探讨了海洋生物活性化合物作为GCK活化剂的潜力。基于结构的虚拟筛选（SBVS）对大约32,000种抗人GCK的海洋天然产物（MNPs）（PDB ID: 1V4S）进行了筛选，确定了4种有希望的候选药物：CMNPD6570、CMNPD5231、SWMDBB001和SWMDBB004。这些MNPs表现出良好的结合亲和力得分（范围从-8.80到-12.62 kcal/mol），并与关键残基（包括Tyr61、Arg63、Thr65、Tyr214和Tyr215）形成关键相互作用。此外，MM-GBSA结合自由能（-89.54 ~ -115.66 kJ/mol）和MM-PBSA结合自由能（-93.05 ~ -306.18 kJ/mol）分析进一步支持了它们的强结合亲和力。药代动力学和毒性预测表明，所有鉴定的MNPs具有良好的药物样特性。300 ns的全原子分子动力学（MD）模拟表明，与天然配体相比，这些化合物的结构稳定性增强。值得注意的是，CMNPD6570和SWMDBB004表现出稳定的GCK结合，RMSD值低，关键残基波动最小。此外，利用主成分（PC）预测的自由能景观（FEL）分析证实了这些相互作用的稳定性。总的来说，这些发现强调了海洋生物活性化合物作为新型GCK激活剂的潜力，为未来的实验验证和T2DM治疗方法的开发奠定了坚实的基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Structure-guided discovery of marine natural products as glucokinase activators for type 2 diabetes mellitus: A computational perspective

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Structure-guided discovery of marine natural products as glucokinase activators for type 2 diabetes mellitus: A computational perspective

Diabetes is a prevalent metabolic disorder and the ninth leading cause of mortality worldwide. Despite the availability of effective hypoglycemic agents, there remains an urgent need for more potent therapeutics with minimal adverse effects. Targeting key metabolic regulators, such as enzymes, transporters, and receptors, offers promising avenues for drug discovery. Glucokinase (GCK), a pivotal enzyme in glucose metabolism, catalyzes the conversion of glucose into glucose-6-phosphate and functions as a glucose sensor, making it a highly attractive therapeutic target for Type 2 Diabetes Mellitus (T2DM). This study investigates the potential of marine-derived bioactive compounds as GCK activators. Structure-based virtual screening (SBVS) of approximately 32,000 marine natural products (MNPs) against human GCK (PDB ID: 1V4S) identified four promising candidates: CMNPD6570, CMNPD5231, SWMDBB001, and SWMDBB004. These MNPs exhibited favorable binding affinity scores (ranging from −8.80 to −12.62 kcal/mol) and formed key interactions with critical residues, including Tyr61, Arg63, Thr65, Tyr214, and Tyr215. Additionally, MM-GBSA binding free energy calculations (−89.54 to −115.66 kcal/mol) and MM-PBSA analysis (−93.05 to −306.18 kJ/mol) further supported their strong binding affinity. Pharmacokinetic and toxicity predictions indicated favorable drug-like properties for all identified MNPs. All-atom molecular dynamics (MD) simulations for 300 ns demonstrated enhanced structural stability of these compounds compared to the native ligand. Notably, CMNPD6570 and SWMDBB004 exhibited stable GCK binding, with low RMSD values and minimal fluctuations in key residues. Furthermore, free energy landscape (FEL) analysis using principal component (PC) projections confirmed the stability of these interactions. Overall, these findings underscore the potential of marine-derived bioactive compounds as novel GCK activators, laying a strong foundation for future experimental validation and the development of therapeutics for T2DM.

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来源期刊

Journal of molecular graphics & modelling 生物-计算机：跨学科应用

CiteScore

5.50

自引率

6.90%

发文量

216

审稿时长

35 days

期刊介绍： The Journal of Molecular Graphics and Modelling is devoted to the publication of papers on the uses of computers in theoretical investigations of molecular structure, function, interaction, and design. The scope of the journal includes all aspects of molecular modeling and computational chemistry, including, for instance, the study of molecular shape and properties, molecular simulations, protein and polymer engineering, drug design, materials design, structure-activity and structure-property relationships, database mining, and compound library design. As a primary research journal, JMGM seeks to bring new knowledge to the attention of our readers. As such, submissions to the journal need to not only report results, but must draw conclusions and explore implications of the work presented. Authors are strongly encouraged to bear this in mind when preparing manuscripts. Routine applications of standard modelling approaches, providing only very limited new scientific insight, will not meet our criteria for publication. Reproducibility of reported calculations is an important issue. Wherever possible, we urge authors to enhance their papers with Supplementary Data, for example, in QSAR studies machine-readable versions of molecular datasets or in the development of new force-field parameters versions of the topology and force field parameter files. Routine applications of existing methods that do not lead to genuinely new insight will not be considered.