Journal of molecular graphics & modelling最新文献_第2页

Unveiling Tamarix articulata phytochemicals as novel natural inhibitors of colon cancer: A holistic drug design and toxicological approach 揭示柽柳植物化学物质作为结肠癌的新型天然抑制剂：整体药物设计和毒理学方法

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-26 DOI: 10.1016/j.jmgm.2025.109267

Abdullah M. Alnuqaydan

Cancer, more specifically, has a strong connection to aberrant kinase activity. Thereby, kinases serve as vital targets for the development of anti-cancer drugs. The ERK2 is a promising therapeutic option for advanced colon cancer treatment. This study seeks to evaluate the experimentally identified phytochemicals from Tamarix articulata for their inhibitory activity on colon cancer. The study employed molecular docking investigation to screen 222 derivatives against ERK2. The findings shortlisted 10 compounds based on the binding affinity score. 3/10 were further selected as the top 3 hits. The top 3 hits are Dicumarol (−9.7 kcal/mol), 2, 3, 9, 10-Tetrahydroxyberbine (−8.8 kcal/mol), and Nafenopin (−8.3 kcal/mol). The AZD0364 (−9.8 kcal/mol) was used as a reference/control in the present study. The compounds were further assessed for pharmacokinetics feature prediction; hence, all the compounds met the Lipinski Rule 5 parameters with no violations observed. The molecular dynamics (MD) simulation trajectory for the ERK2-ligand complexes yielded satisfactory results, characterized by a strong interaction and intermolecular conformational stability. The mean root mean square deviation (RMSD) noted for the top 3 complexes was <2 Å. The post-MD simulation analysis was performed to enhance and validate the efficacy of the complexes. The principal component analysis (PCA) analysis and hydrogen bonding assessment depicted 2, 3, 9, 10-Tetrahydroxyberbine as the most stable with no greater conformational variations, while the same complex created the most strong and stable bond with a total no-of frames 954, surpassing Dicumarol and Nefenopin. The unique salt bridges were observed in the novel ERK2-ligand complexes as per the comparative analysis with the control (Glu64-Lys147 and Glu43-Lys82, Glu297-Lys268, Glu203-Lys100, and Asp266-Lys268). The secondary structure studies plot depicted that all the ERK2-ligand complexes were stable. The MM-GBSA and MM-PBSA scores ranked Dicumarol as the top-notch compound (−67.44 kcal/mol and −68.66 kcal/mol). The WaterSwap considerably polishes our comprehensive simulation findings. Therefore, these findings offer a possible foundation for the exploration of inhibitors that target the ERK2 gene in vitro and in vivo, which might contribute to a landmark in cancer research.

更具体地说，癌症与异常的激酶活性有很强的联系。因此，激酶是开发抗癌药物的重要靶点。ERK2是晚期结肠癌治疗的一种很有前景的治疗选择。本研究旨在评价实验鉴定的柽柳植物化学物质对结肠癌的抑制作用。本研究采用分子对接法筛选了222个抗ERK2衍生物。研究结果根据结合亲和力评分列出了10种化合物。3/10被进一步选为前3名。前3名分别是双umarol（−9.7 kcal/mol）、2,3,9,10 - tetrahydroxyberbine（−8.8 kcal/mol）和Nafenopin（−8.3 kcal/mol）。本研究以AZD0364（−9.8 kcal/mol）为对照。进一步评估化合物的药代动力学特征预测；因此，所有化合物均符合Lipinski规则5参数，无违和现象。erk2 -配体复合物的分子动力学（MD）模拟轨迹取得了令人满意的结果，具有强相互作用和分子间构象稳定性的特点。前3个配合物的均方根偏差（RMSD）为<；2 Å。进行了md后模拟分析，以增强和验证配合物的功效。主成分分析（PCA）和氢键评价表明2,3,9,10 - tetrahydroxyberbine是最稳定的，没有更大的构象变化，而相同的配合物产生了最强大和稳定的键，总帧数为954，超过了Dicumarol和Nefenopin。通过与对照（Glu64-Lys147和Glu43-Lys82、Glu297-Lys268、Glu203-Lys100和Asp266-Lys268）的比较分析，在新的erk2配体复合物中观察到独特的盐桥。二级结构研究表明，所有的erk2配体配合物都是稳定的。MM-GBSA和MM-PBSA评分将Dicumarol列为最高的化合物（- 67.44 kcal/mol和- 68.66 kcal/mol）。WaterSwap大大改善了我们的综合模拟结果。因此，这些发现为在体外和体内探索靶向ERK2基因的抑制剂提供了可能的基础，这可能有助于癌症研究的里程碑。

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引用次数: 0

Breaking resistance with machine and deep learning: A computational intelligence hunt for AmvR (TetR) inhibitors in Acinetobacter baumannii 用机器和深度学习打破耐药性：鲍曼不动杆菌AmvR （TetR）抑制剂的计算智能搜索。

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-22 DOI: 10.1016/j.jmgm.2025.109261

Yahya A. Almutawif , Saad Amin , Sajjad Ahmad , Kalsoom Khan , Asad Ullah , Abu Nasar Siddique , Faisal Ahmad

Multidrug-resistant Acinetobacter baumannii infections have driven the development of innovative therapeutic approaches to address global challenges. The present study reported that the protein belonging to the TetR family regulator AmvR from A. baumannii is bound to spermidine. Here, quantitative structure-activity relationship (QSAR) models developed from a ChEMBL dataset were used to perform an initial screening of a library of 10,860 natural chemical compounds, along with their reported minimum inhibitory concentration (MIC) scores. Machine learning models, including RF, SVM, KNN, and XGBoost, were implemented for compound classification. An RF model was selected that achieved a 96 % accuracy score on the test set. A deep learning model, CNN, was built, and a structure-based virtual screening approach was applied against A. baumannii to assess how similar these molecules are to drug likeness. In silico pharmacokinetic analysis was performed for the top candidates, including binding energy evaluation of protein-ligand docking with scores of −10.6 kcal/mol, −10.4 kcal/mol, and a control with −6 kcal/mol. Absorption, distribution, metabolism, and excretion (ADME) properties for CHEMBL-560977, CHEMBL-551116, and the control complex were also noted. Additionally, the binding mechanism was elucidated through molecular dynamics simulations over 500 ns, with binding free energy analysis (MMGBSA/PBSA) showing results of −120.55 kcal/mol, −94.99 kcal/mol, and −90.65 kcal/mol. Dynamic cross-correlation matrix (DCCM), radial distribution function (RDF), and hydrogen bonding (H-bonds) analyses were conducted, along with principal component analysis (PCA) and free energy landscape (FEL) clustering for the selected complexes. Secondary structure analysis and salt bridge assessments indicated that the newly discovered compounds are more promising than the currently available drugs. According to all docking and MD simulation results, the ligand-bound protein exhibits promising and stable behavior. Lastly, the selected compounds are recommended for further experimental studies and could serve as potent inhibitors of A. baumannii infection.

耐多药鲍曼不动杆菌感染推动了创新治疗方法的发展，以应对全球挑战。本研究报道了鲍曼不动杆菌中属于TetR家族调节因子AmvR的蛋白与亚精胺结合。在这里，从ChEMBL数据集开发的定量构效关系（QSAR）模型用于对10,860种天然化合物库进行初步筛选，以及它们报告的最低抑制浓度（MIC）分数。采用RF、SVM、KNN、XGBoost等机器学习模型进行复合分类。选择的RF模型在测试集上获得了96%的准确率分数。建立了一个深度学习模型CNN，并对鲍曼假单胞杆菌应用了基于结构的虚拟筛选方法，以评估这些分子与药物相似度的相似程度。在计算机上对候选药物进行了药代动力学分析，包括蛋白质-配体对接结合能评估，得分为-10.6 kcal/mol, -10.4 kcal/mol，对照为-6 kcal/mol。还记录了CHEMBL-560977、CHEMBL-551116和对照配合物的吸收、分布、代谢和排泄（ADME）特性。结合自由能（MMGBSA/PBSA）分析结果分别为-120.55 kcal/mol、-94.99 kcal/mol和-90.65 kcal/mol。采用动态互相关矩阵（DCCM）、径向分布函数（RDF）、氢键（h -键）分析、主成分分析（PCA）和自由能景观聚类（FEL）对所选配合物进行聚类分析。二级结构分析和盐桥评价表明，新发现的化合物比现有的药物更有前景。根据所有对接和MD模拟结果，配体结合蛋白表现出良好的稳定行为。最后，所选化合物被推荐用于进一步的实验研究，并可能作为鲍曼不动杆菌感染的有效抑制剂。

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引用次数: 0

Quantum transport in DNA modulated by a Schiff base ligand: The role of binding and electronic structure changes from DFT–NEGF–MD simulations 席夫碱基配体调节DNA中的量子传输：DFT-NEGF-MD模拟中结合和电子结构变化的作用。

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-22 DOI: 10.1016/j.jmgm.2025.109263

Tuncay Karakurt , Alaaddin Cukurovali , Hashem Mohammad , Ibrahim Yilmaz

DNA has emerged as a promising molecular system for nanoscale electronics owing to its self–assembly, programmability, and π–orbital delocalization. Here, we investigate the quantum charge transport behavior of a canonical 12–base–pair B–DNA duplex (RCSB ID: 102d, 5′–CGCAAATTTGCG–3′) and its Schiff-base ligand–bound complexes. The ligand, 2–methoxy–4–((2–(4–(3–methyl–3–phenylcyclobutyl)thiazol–2–yl)hydrazono)methyl)phenol (C₂₂H₂₃N₃O₂S), was synthesized and structurally characterized via NMR and single–crystal X–ray diffraction. Quantum transport properties were computed using density functional theory combined with the nonequilibrium Green's function (DFT–NEGF) formalism including decoherence corrections. Transmission spectra Teff(E) and conductance G(E_F) were analyzed for bare and ligand–modified DNA systems. HOMO orbitals were found to localize strongly on the ligands, reducing conductance by ∼67–76 % relative to 102d. Classical molecular dynamics and MM/GBSA binding‐energy analyses were used to explore potential relationships between ligand binding strength, orbital localization, and transport suppression. Within the statistical uncertainty of the free‐energy estimates, the calculations support a qualitative trend in which configurations with stronger enthalpic stabilization tend to exhibit enhanced HOMO localization and reduced conductance. However, the absence of a simple one-to-one correlation indicates that electronic transport is governed more by the specific binding mode and the resulting orbital redistribution than by the magnitude of binding affinity alone. These results therefore suggest a complex interplay between binding thermodynamics and quantum conductance, highlighting the dual role of ligand intercalation in stabilizing DNA while modulating its electronic delocalization.

DNA由于其自组装性、可编程性和π轨道离域性而成为纳米电子学研究的重要分子系统。本文研究了典型的12碱基对B-DNA双工（RCSB ID: 102d, 5'- cgcaaatttgg -3'）及其希夫碱配体结合配合物的量子电荷传输行为。合成了配体2-甲氧基-4-(（2-（4-（3-甲基-3-苯基环丁基）噻唑-2-基）腙-甲基）苯酚（C22H23N3O2S），并通过核磁共振和单晶x射线衍射对其进行了结构表征。利用密度泛函理论结合非平衡格林函数（DFT-NEGF）计算了量子输运性质，包括退相干校正。分析了裸DNA和配体修饰DNA的透射光谱Teff(E)和电导G（EF）。发现HOMO轨道在配体上强烈定位，相对于102d，电导降低了~ 67- 76%。经典分子动力学和MM/GBSA结合能分析用于探索配体结合强度、轨道定位和运输抑制之间的潜在关系。在自由能估计的统计不确定性范围内，计算支持一个定性趋势，即具有更强焓稳定的构型倾向于表现出增强的HOMO局域化和降低的电导。然而，缺乏简单的一对一相关性表明，电子输运更多地受特定的结合模式和由此产生的轨道重新分配的支配，而不仅仅受结合亲和力的大小的支配。因此，这些结果表明结合热力学和量子电导之间存在复杂的相互作用，突出了配体嵌入在稳定DNA和调节其电子离域方面的双重作用。

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引用次数: 0

Theoretical study of graphenylene -like boron phosphide monolayer as an encouraging anode electrode material for Ca-ion batteries 类石墨烯类磷化硼单层作为钙离子电池正极材料的理论研究。

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-22 DOI: 10.1016/j.jmgm.2025.109265

Qamar Abuhassan , Ahmed Aldulaimi , Omayma Salim Waleed , Subbulakshmi Ganesan , Kavitha V , Laxmidhar Maharana , Renu Sharma , Khalmurat Iliev , Zukhra Atamuratova , D. Yolchiev , Aseel Smerat

Through employing first-principles calculations (DFT), compatibility of BP-graphenylene (g-BP) has been assessed for Ca-ion batteries (CIBs). Throughout our assessments, we examine parameters including the adsorption energy (E_ad) of g-BP when combined with Ca adatoms, along with theoretical capacity and diffusion barrier (E_bar) and of Ca²⁺ over such particular surface. Findings reveal that g-BP boasts substantially greater Ca-ion storage capacities at 947.22 mAh/g, surpassing those of conventional graphite anodes and rest of C materials. Additionally, E_bar value for Ca²⁺ has been computed to be 91 meV on g-BP monolayer. Calculated E_bar values align with the theoretically reported range for commercial anodes. Calculated open-circuit voltage (OCV) values correspond to the range 0.2–0.81 V considered suitable for negative electrode materials. Moreover, E_ads values of Ca on the g-BP surface reach as high as −1.59 eV, effectively mitigating the inadvertent decomposition of Ca. Outcomes accentuate the application of the g-BP sheet as a promising candidate for negative electrode materials in CIBs.

通过第一性原理计算（DFT），评价了bp -石墨烯（g-BP）在钙离子电池（cib）中的相容性。在整个评估过程中，我们检查了g-BP与Ca结合时的吸附能（Ead），以及理论容量和扩散屏障（Ebar）和Ca2+在这种特定表面上的吸附能。结果表明，g- bp具有更大的ca离子存储容量，达到947.22 mAh/g，超过了传统的石墨阳极和其他C材料。此外，计算出Ca2+在g-BP单层上的Ebar值为91 meV。计算出的Ebar值与商业阳极的理论报告范围一致。计算的开路电压（OCV）值对应于0.2-0.81 V的范围，被认为适用于负极材料。此外，g-BP表面的Ca的Eads值高达-1.59 eV，有效地减轻了Ca的无意分解。结果强调了g-BP片作为cib负极材料的有希望的候选材料的应用。

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引用次数: 0

Computational studies of target-specific radiopharmaceuticals for theranostics 用于治疗学的靶向放射药物的计算研究

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-20 DOI: 10.1016/j.jmgm.2025.109264

Silvia Gervasoni, Camilla Guccione, Giuliano Malloci

Radiopharmaceuticals are key tools in nuclear medicine, enabling both diagnostic imaging and targeted therapy for conditions such as cancer and neurological disorders. The integration of computational techniques in the drug-discovery process, such as molecular docking and molecular dynamics simulations, contributes to the development of this class of compounds. Here we review recent computational studies on radiopharmaceuticals acting on different targets: receptors, enzymes, and transporters. Several receptors such as chemokine receptor 4, neurokinin-1, metabotropic glutamate receptor, and gastrin-releasing peptide receptor have been investigated using molecular simulations to optimize ligand binding and enhance receptor targeting. Enzymes like prostate-specific membrane antigen and fibroblast activation protein

α

have been investigated in silico for their interaction with novel radiopharmaceutical inhibitors. Additionally, transporter proteins such as glucose transporters have been explored for their role in cancer metabolism and imaging applications. Advanced computational studies, including quantum mechanics calculations and free energy estimations, have contributed to our understanding of radiopharmaceutical binding modes and stability at the molecular level of detail. The review highlights the potential of computational approaches for cost-effective design of next-generation theranostic agents, emphasizing the importance of molecular databases in ligand-based drug discovery and artificial intelligence-based drug design.

放射性药物是核医学的关键工具，可用于癌症和神经系统疾病等疾病的诊断成像和靶向治疗。在药物发现过程中集成计算技术，如分子对接和分子动力学模拟，有助于这类化合物的发展。在这里，我们回顾了最近关于放射性药物作用于不同靶点的计算研究：受体、酶和转运体。趋化因子受体4、神经激肽-1、代谢性谷氨酸受体和胃泌素释放肽受体等受体已通过分子模拟研究优化配体结合和增强受体靶向性。前列腺特异性膜抗原和成纤维细胞活化蛋白α等酶与新型放射性药物抑制剂的相互作用已经在硅片上进行了研究。此外，转运蛋白如葡萄糖转运蛋白在癌症代谢和成像应用中的作用已被探索。先进的计算研究，包括量子力学计算和自由能估计，有助于我们在分子水平上对放射性药物结合模式和稳定性的理解。该综述强调了计算方法在低成本设计下一代治疗药物方面的潜力，强调了分子数据库在基于配体的药物发现和基于人工智能的药物设计中的重要性。

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引用次数: 0

Pharmacoinformatic discovery of plant-derived BRD4 inhibitors as potential therapeutic agents for leukemia 植物源BRD4抑制剂作为白血病潜在治疗剂的药物信息学发现。

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-18 DOI: 10.1016/j.jmgm.2025.109262

Anjana C. Lalu , Bristow Ben Joseph , Varun T.K., Amritha Thaikkad, Leona Dcunha, Rajesh Raju, Abhithaj Jayanandan

Leukemia is a type of blood cancer that occurs when abnormal white blood cells grow too quickly. This uncontrolled growth begins in the bone marrow, where blood cells are produced. Leukemia remains a major health concern due to its high incidence and difficult prognosis. It is the most common type of cancer in children and ranks among the top 15 most prevalent cancers in adults, as reported by the World Health Organization. Several BRD4 inhibitors have shown promising potential as treatments for leukemia. These molecules function by blocking BRD4's interaction with acetylated histones, specifically targeting key amino acid residue ASN140. By disrupting this binding, they offer a potentially more effective therapeutic approach in combating leukemia. Current cancer treatments, such as chemotherapy and targeted therapies like JQ1, frequently come with side effects and toxicity, which highlights the need for safer alternatives. In our study, we explored plant-derived natural compounds that might offer anticancer benefits while being easier on the body. Using advanced techniques like pharmacophore-based virtual screening and ADMET analysis, we identify potential candidates. Molecular docking and dynamics simulations further revealed strong and stable interactions between BRD4 protein and these compounds. Notably, Calyxins C had the best interaction profile, with a docking score of −12.756 kcal/mol and a binding free energy of −85.32 kcal/mol. For Calyxins A, the binding free energy was −72.53 kcal/mol with a docking score of −10.132 kcal/mol, while for Deoxycalyxin A, it was −73.03 kcal/mol with a docking score of −10.162 kcal/mol. Our research indicates that these natural compounds, Calyxins C, Calyxins A, and Deoxyocalyxin A, exhibit higher stability and favorable interaction profiles, which could be effective and less toxic drug leads for leukemia treatment, paving the way for future experimental validation and clinical studies.

白血病是一种血癌，当异常白细胞生长过快时就会发生。这种不受控制的生长始于产生血细胞的骨髓。白血病由于发病率高、预后困难，一直是一个主要的健康问题。根据世界卫生组织的报告，它是儿童中最常见的癌症类型，也是成人中最常见的15种癌症之一。几种BRD4抑制剂已显示出治疗白血病的良好潜力。这些分子通过阻断BRD4与乙酰化组蛋白的相互作用发挥作用，特别是针对关键氨基酸残基ASN140。通过破坏这种结合，他们为对抗白血病提供了一种潜在的更有效的治疗方法。目前的癌症治疗，如化疗和靶向治疗，如JQ1，经常有副作用和毒性，这突出了需要更安全的替代品。在我们的研究中，我们探索了植物衍生的天然化合物，这些化合物可能提供抗癌益处，同时对身体更容易。使用先进的技术，如基于药物团的虚拟筛选和ADMET分析，我们确定潜在的候选人。分子对接和动力学模拟进一步揭示了BRD4蛋白与这些化合物之间强而稳定的相互作用。其中，Calyxins C的相互作用曲线最佳，对接分数为-12.756 kcal/mol，结合自由能为-85.32 kcal/mol。Calyxins A的结合自由能为-72.53 kcal/mol，对接分数为-10.132 kcal/mol； Deoxycalyxin A的结合自由能为-73.03 kcal/mol，对接分数为-10.162 kcal/mol。我们的研究表明，这些天然化合物Calyxins C、Calyxins A和脱氧Calyxins A具有较高的稳定性和良好的相互作用谱，可能是有效且毒性较小的白血病治疗药物先导物，为未来的实验验证和临床研究铺平了道路。

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引用次数: 0

A quantum chemical investigation of potential applicability of X12Y12 (X= B, Al, C; Y= N, P, C) nanocages for efficient removal of levofloxacin through water 量子化学研究了X12Y12 （X= B, Al， C； Y= N， P， C）纳米笼在水中高效去除左氧氟沙星的潜在适用性。

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-18 DOI: 10.1016/j.jmgm.2025.109260

Seyda Aydogdu

In the last years, growing human populations and economies have led to increasing environmental pollution, especially in water. Due to the adverse effects of antibiotics in the water environment, public concerns have increased about the health issue. For this reason, removal of antibiotic pollutants from the water environment is urgently needed. This work has been conducted in order to find a suitable adsorbent nanocage structure from X₁₂Y₁₂ (B₁₂N₁₂, Al₁₂N₁₂, B₁₂P₁₂, Al₁₂P₁₂, C₂₄) for removing levofloxacin antibiotic by using Density Functional Theory. The favorable adsorption processes are determined via adsorption energies and thermodynamic results for various orientations of levofloxacin onto the nanocages. The electronic nature of the adsorption processes is investigated with the help of Mulliken analysis, Natural Bond Orbital Analysis, and Quantum Theory of Atoms in Molecules. The reactivity and sensitivity investigation of the nanocage and levofloxacin complex systems is elucidated with global reactivity indices, Frontier Molecular Orbitals, Density of States spectra, and work function. The change of dipole moment values after adsorption are determined. The spontaneous characters of adsorption processes are determined. Furthermore, the number of LEV molecules, the water medium and the saline content of water effects the adsorption of LEV have been determined. The outcomes of this study demonstrate that Al₁₂N₁₂ and Al₁₂P₁₂ nanocages can be useable for effective removal of levofloxacin. The results of this study will be a novel contribution for further studies in order to remove levofloxacin effectively.

在过去的几年里，不断增长的人口和经济导致了越来越多的环境污染，特别是在水方面。由于抗生素对水环境的不良影响，公众对健康问题的关注日益增加。因此，迫切需要从水环境中去除抗生素污染物。本研究旨在利用密度泛函理论，从X12Y12 （B12N12, Al12N12, B12P12, Al12P12, C24）中寻找合适的吸附纳米笼结构，以去除左氧氟沙星抗生素。通过吸附能和热力学结果确定了左氧氟沙星在纳米笼上不同取向的吸附过程。利用Mulliken分析、自然键轨道分析和分子原子量子理论研究了吸附过程的电子性质。利用全局反应性指数、前沿分子轨道、态密度光谱和功函数对纳米笼-左氧氟沙星配合物体系的反应性和灵敏度进行了研究。测定了吸附后偶极矩值的变化。确定了吸附过程的自发特性。此外，还确定了LEV分子数、水介质和水中含盐量对其吸附的影响。本研究结果表明，Al12N12和Al12P12纳米笼可用于有效去除左氧氟沙星。本研究结果将为进一步有效去除左氧氟沙星的研究做出新的贡献。

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引用次数: 0

Machine learning-guided repurposing of FDA-approved quinolones as dual cholinesterase inhibitors: A multi-level docking, molecular dynamics, DFT, and SHAP-based analysis fda批准的喹诺酮类药物作为双胆碱酯酶抑制剂的机器学习指导：多层次对接，分子动力学，DFT和基于shap的分析。

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-15 DOI: 10.1016/j.jmgm.2025.109259

Cüneyt Türkeş

Alzheimer's disease (AD) involves progressive cholinergic degeneration, with acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) playing key enzymatic roles in its pathology. In this study, we computationally repurposed four FDA-approved quinolone antibiotics, Norfloxacin, Sparfloxacin, Gatifloxacin, and Nalidixic acid, as potential dual-site cholinesterase (ChE) inhibitors using a hybrid in vitro/in silico workflow. Enzyme inhibition assays identified Norfloxacin as the most potent AChE inhibitor (K_I = 1.08 μM), while all compounds displayed non-competitive inhibition toward BChE. Molecular docking and MM-GBSA binding free energy analyses revealed key interactions within the catalytic gorge of AChE, supported by hydrogen bonding with Phe295 and Arg296, as well as π–π contacts with Tyr124. Density functional theory computations highlighted the influence of frontier orbital distribution on binding affinity, particularly for Norfloxacin and Sparfloxacin. An explicit-solvent molecular dynamics simulation of the AChE–Norfloxacin complex further confirmed the stability of the docking-derived binding mode over 100 ns. In an exploratory fashion, SHAP-based machine learning models were applied to a descriptor set derived from QikProp, SwissADME, and Jaguar outputs, suggesting that BBB-related indices and HOMO energy contribute to AChE inhibition, whereas the energy gap is more relevant for BChE; these trends, however, are constrained by the small four-compound dataset and should be regarded as hypothesis-generating. In silico ADME/Tox profiling indicated favorable oral drug-like properties, low predicted CYP450 inhibition liabilities, and physicochemical profiles compatible with CNS-oriented optimization, although passive BBB permeability was not predicted to be high. Finally, systems-level enrichment (STRING, GeneCards) provided a qualitative network context linking ACHE and BCHE to neurodegeneration. Together, these data position Norfloxacin and Sparfloxacin as computationally prioritised candidates whose ChE-related repurposing potential warrants further validation in dedicated cellular and in vivo models.

阿尔茨海默病（AD）涉及进行性胆碱能变性，乙酰胆碱酯酶（AChE）和丁基胆碱酯酶（BChE）在其病理中起关键作用。在这项研究中，我们使用体外/室内混合工作流程，计算重新利用四种fda批准的喹诺酮类抗生素，诺氟沙星，斯帕沙星，加替沙星和萘利地酸，作为潜在的双位点胆碱酯酶（ChE）抑制剂。酶抑制实验表明，诺氟沙星是最有效的AChE抑制剂（KI = 1.08 μM），而所有化合物对BChE均表现出非竞争性抑制作用。分子对接和MM-GBSA结合自由能分析揭示了AChE催化通道内的关键相互作用，包括与Phe295和Arg296的氢键，以及与Tyr124的π-π接触。密度泛函理论计算强调了前沿轨道分布对结合亲和力的影响，特别是对诺氟沙星和斯帕沙星。乙酰氨基酸-诺氟沙星配合物的显式溶剂分子动力学模拟进一步证实了对接衍生的结合模式在100 ns以上的稳定性。以探索性的方式，基于shap的机器学习模型应用于来自QikProp、SwissADME和Jaguar输出的描述符集，表明bbb相关指数和HOMO能量有助于AChE抑制，而能量缺口与BChE更相关；然而，这些趋势受到小的四复合数据集的限制，应该被视为假设生成。在硅ADME/Tox分析显示良好的口服药物样性质，低预测CYP450抑制负荷，和物理化学特征兼容的cns导向优化，虽然被动血脑屏障渗透率预测不高。最后，系统级富集（STRING, GeneCards）提供了将ACHE和BCHE与神经变性联系起来的定性网络上下文。总之，这些数据将诺氟沙星和斯帕沙星定位为计算优先的候选药物，其与che相关的再利用潜力值得在专门的细胞和体内模型中进一步验证。

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引用次数: 0

A computational study integrating antiviral peptide mediated inhibition of trafficking complex in Sesbania Mosaic Virus 整合抗病毒肽介导的田菁花叶病毒运输复合物抑制的计算研究。

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-15 DOI: 10.1016/j.jmgm.2025.109258

Jyotilipsa Mohanty, Ayaluru Murali

Plant viruses pose a serious threat to global agriculture and although chemical, genetic, and biological control strategies exist, but each method have limitations in effectiveness and sustainability. Recently, the use of microbial peptides for curbing the movement of plant viruses has gained momentum. In this work, five peptides viz. Peptamine, indolicidin 10R, indolicidin 11R, Recombinant Thanatin (RT) and Recombinant Chimeric Lactoferricin + Lactoferrampin (RCLL), were identified and analysed for their role in disrupting the virus movement. The Sesbania Mosaic Virus (SeMV) is known to use a trafficking complex (a heteroprotein complex consisting of movement protein (MP), RdRp, VPg, and P10) for its intercellular movement. In this work, the ability of these peptides in binding to the major constituents of the trafficking complex (the MP and the RdRp) and their ability to disrupt the formation of trafficking complex was analysed using in silico tools. All five peptides were found to be disrupting the formation of the trafficking complex. Our findings suggest that these peptides can serve as potential antiviral agents by interfering with essential viral functions. This study provides new insights into peptide-based inhibition of plant viruses, offering an alternative to conventional control strategies.

植物病毒对全球农业构成严重威胁，尽管存在化学、遗传和生物防治策略，但每种方法在有效性和可持续性方面都有局限性。近年来，利用微生物肽抑制植物病毒的传播已成为研究热点。在这项工作中，鉴定并分析了五种肽，即Peptamine， indolicidin 10R, indolicidin 11R，重组Thanatin （RT）和重组嵌合乳铁蛋白+乳铁蛋白（RCLL），它们在破坏病毒运动中的作用。已知田菁花叶病毒（SeMV）使用运输复合体（由运动蛋白（MP）、RdRp、VPg和P10组成的异蛋白复合体）进行细胞间运动。在这项工作中，使用硅工具分析了这些肽与运输复合物（MP和RdRp）的主要成分结合的能力以及它们破坏运输复合物形成的能力。所有五种多肽都被发现破坏了运输复合物的形成。我们的研究结果表明，这些肽可以通过干扰基本的病毒功能作为潜在的抗病毒药物。该研究为基于多肽的植物病毒抑制提供了新的见解，为传统的控制策略提供了替代方案。

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引用次数: 0

In silico identification of food-grade cooling compounds targeting TRPM8 and TRPA1: A dual-target approach 针对TRPM8和TRPA1的食品级冷却化合物的硅基鉴定：双靶标方法。

IF 3 4区生物学 Q2 BIOCHEMICAL RESEARCH METHODS

Journal of molecular graphics & modelling

Pub Date : 2025-12-13 DOI: 10.1016/j.jmgm.2025.109257

Zhongwei Zhang , Jun Wang , Yu Liu , Xiangyu Li , Hao Shu , Jideng Chu , Zhangqi Chai , Junsong Xiao , Guangwen Ma , Hua Wu

Background

Oral mucosa is susceptible to pathological changes, including burning sensation, erythema, and inflammation, when exposed to thermal, mechanical, or chemical stimuli. These changes significantly impact oral comfort and health. To address the need for oral cooling agents, this study targets both TRPM8 and TRPA1 channels. We established a “computation-screening-validation” system using homology modeling and virtual screening to identify potential cooling agents from 555 natural flavorings approved for food use in China.

Results

High-quality homology models of TRPM8 and TRPA1 were constructed. Multi-stage virtual screening was then performed using molecular docking. This process incorporated pharmacokinetic properties, key physicochemical properties (water solubility and lipophilicity), and Protox3.0 toxicity predictions. The structural stability of promising ligand-target complexes was further evaluated via molecular dynamics simulations. The screening identified α-Terpineol, cis-Jasmone, and Benzyl Salicylate as promising candidates. These compounds demonstrated superior predicted binding affinities for both targets compared to other screened compounds and favorable safety profiles. Molecular dynamics simulations confirmed stable binding and structural compactness of these compounds within the TRPM8 and TRPA1 binding sites.

Conclusions

This dual-target in silico approach offers an efficient, systematic way to identify safe and effective cooling agents. It provides valuable insights for the development of temperature-sensing modulators by highlighting compounds that can simultaneously activate TRPM8 and TRPA1.

背景：当暴露于热、机械或化学刺激时，口腔黏膜易发生病理变化，包括烧灼感、红斑和炎症。这些变化显著影响口腔舒适和健康。为了解决口服冷却剂的需求，本研究同时针对TRPM8和TRPA1通道。我们建立了一个“计算-筛选-验证”系统，利用同源性建模和虚拟筛选，从中国批准用于食品的555种天然香料中筛选出潜在的冷却剂。结果：构建了高质量的TRPM8和TRPA1同源性模型。然后利用分子对接进行多阶段虚拟筛选。这个过程包括药代动力学性质、关键的物理化学性质（水溶性和亲脂性）和Protox3.0毒性预测。通过分子动力学模拟进一步评价了有前途的配体-靶配合物的结构稳定性。筛选结果表明α-松油醇、顺式茉莉酮和水杨酸苄酯是较有前途的候选物质。与其他筛选的化合物相比，这些化合物对这两个靶点的预测结合亲和力和良好的安全性。分子动力学模拟证实了这些化合物在TRPM8和TRPA1结合位点内的稳定结合和结构紧密性。结论：这种双靶点硅片方法提供了一种高效、系统的方法来鉴定安全有效的冷却剂。它通过突出可以同时激活TRPM8和TRPA1的化合物，为温度传感调节剂的开发提供了有价值的见解。

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引用次数: 0