Journal of Biomolecular Structure & Dynamics最新文献_第10页

Molecular insights into atopic dermatitis treatment: investigating bioactive compounds in Aceh's traditional fermented coconut oil. 分子洞察到特应性皮炎治疗：研究亚齐传统发酵椰子油中的生物活性化合物。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-07 DOI: 10.1080/07391102.2025.2487195

Rima Hayati, Endang Lukitaningsih, Nanda Earlia, Mohamed El-Shazly, Rinaldi Idroes

{"title":"Molecular insights into atopic dermatitis treatment: investigating bioactive compounds in Aceh's traditional fermented coconut oil.","authors":"Rima Hayati, Endang Lukitaningsih, Nanda Earlia, Mohamed El-Shazly, Rinaldi Idroes","doi":"10.1080/07391102.2025.2487195","DOIUrl":"https://doi.org/10.1080/07391102.2025.2487195","url":null,"abstract":"Simplah (SM) and pliek (PL) oils are derived from the traditional fermentation process of coconut meat, a practice in Aceh, Indonesia, for generations. We studied their chemical composition and interactions with proteins linked to atopic dermatitis (AD), causing inflammation and allergies. Gas chromatography-mass spectrometry (GC-MS) analysis of SM and PL from five coconut plantations in Aceh revealed 53 compounds with a similarity index (SI) ≥ 800. Peroxide and iodine values met standards, but moisture and free fatty acid content were slightly high. Phenolic and flavonoid content are correlated with antioxidant activity. Molecular docking showed l-(+)-ascorbic acid 2,6-dihexadecanoate (PN32) had high binding affinity to IL2 (-8.2801 kcal/mol), JNK1 (-9.5087 kcal/mol), TNF-α (-7.1581 kcal/mol), and ERK2 (-7.9420 kcal/mol). PN32 had significant inhibitory activity against JNK1 but lower stability than the control native ligand (CNL). It can be stated that SM and PL have potential as topical anti-inflammatory and immunosuppressive agents in AD.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-16"},"PeriodicalIF":2.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In silico approach to screen anti-inflammatory phytochemicals: targeting cytosolic phospholipase A₂ and phospholipase C. 筛选抗炎植物化学物质的硅方法：针对胞质磷脂酶A2和磷脂酶C。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-07 DOI: 10.1080/07391102.2025.2487194

Kunal Kumar, Arun Kumar Malaisamy, Rajat Sharma, Kunal Ranjan, Raghunath Satpathy, Rajani Sharma

{"title":"In silico approach to screen anti-inflammatory phytochemicals: targeting cytosolic phospholipase A2 and phospholipase C.","authors":"Kunal Kumar, Arun Kumar Malaisamy, Rajat Sharma, Kunal Ranjan, Raghunath Satpathy, Rajani Sharma","doi":"10.1080/07391102.2025.2487194","DOIUrl":"https://doi.org/10.1080/07391102.2025.2487194","url":null,"abstract":"Phospholipase A2 (PLA2) have various inflammatory responses by catalysing the release of arachidonic acid and lysophospholipids from membrane phospholipids. Amongst PLA2 variants, cytosolic PLA2 (cPLA2) is central to inflammation, while phospholipase C (PLC) is involved in macrophage-mediated inflammation, significant in various infectious diseases and cancer. Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to prevent inflammation by inhibiting COX 1 and COX 2 enzymes but have several side effects. They affect the gastric mucosa wall, causing stomach and duodenal ulcers. This necessitates desirable alternative enzymes inhibitor with less side effects. In the present study, 57 phytochemicals possessing PLA2 inhibiting properties were screened and compared with chemically synthesised Varespladib. Based on pharmacological activity as analysed from Way2Drugs server, p-Coumaric acid suited best phytochemical against PLA2 and PLC. Molecular docking using HADDOCK server for p-Coumaric acid and reference compound Varespladib exhibited binding score of -51.3 ± 1.4 and -32.3 ± 1.5 with PLA2 respectively whereas displayed binding score of -55.6 ± 3.2 and -31.4 ± 1.3 respectively with PLC. Further, the fact was validated by a comparative 250 ns molecular dynamics (MD) simulation using the Desmond package and MM-GBSA experiments were carried out to analyse the thermodynamic nature of receptor-ligand complex. The MD simulation showed that the phytochemical p-Coumaric acid exhibited strong interactions with cPLA2 and interacted moderately with PLC during the simulation. However, the reference molecule Varespladib was observed to be interacted strongly with cPLA2 and feebly with the PLC. This is the first report on the strong efficacy of p-Coumaric acid against cPLA2.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-10"},"PeriodicalIF":2.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795503","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Homology modeling, molecular docking and MD simulations study of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as sigma-2 receptor ligands. 6,7-二甲氧基-1,2,3,4-四氢异喹啉衍生物作为sigma-2受体配体的同源性建模、分子对接和MD模拟研究。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-07 DOI: 10.1080/07391102.2025.2480273

Vishakha Chaudhary, Shubhra Chaturvedi, Anju Wadhwa, Presenjit Verma, Divya Gautam, Deepika Sharma, Aastha Garg, Vishal Singh, Rupesh Kumar, Anil K Mishra

{"title":"Homology modeling, molecular docking and MD simulations study of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as sigma-2 receptor ligands.","authors":"Vishakha Chaudhary, Shubhra Chaturvedi, Anju Wadhwa, Presenjit Verma, Divya Gautam, Deepika Sharma, Aastha Garg, Vishal Singh, Rupesh Kumar, Anil K Mishra","doi":"10.1080/07391102.2025.2480273","DOIUrl":"https://doi.org/10.1080/07391102.2025.2480273","url":null,"abstract":"The sigma-2 receptor has gathered attention as a promising target for cancer diagnosis and therapy since biochemical studies have evidenced the presence of the receptor in highly proliferating tumor cells. Computational drug design can help create targeted ligands against sigma-2, but a three-dimensional receptor structure is required as input. This study aims to develop a homology model of the human sigma-2 receptor. The template protein bovine sigma-2 (7m93) was aligned with the query sequence (Q5BJF2) to generate five models. These models were screened using potential energy parameters and molecular dynamics, with the model having the lowest energy and maximum stability being validated using stereo chemical parameters. The accepted model had 95.9% residues in allowed regions of the Ramachandran plot and an overall quality factor of 87.2611%. The model was tested using correlation analysis (R2= 0.744) of docking score and literature values of pKi. In addition, the model is used to understand the binding pattern of emerging selective 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline scaffold-based derivatives for designing ligands. The molecular dynamics studies of the model and ligand-bound model were performed for 100 ns to study the stability of the complexes, and the interactions compared with the known antagonist of sigma 2.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-15"},"PeriodicalIF":2.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795565","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Understanding of ATP-lid conformational dynamics in the N-terminal domain of Hsp90 and its mutants by use of a computational biochemistry approach. 利用计算生物化学方法了解Hsp90及其突变体n端结构域的ATP-lid构象动力学。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-07 DOI: 10.1080/07391102.2025.2487202

Keigo Gohda

{"title":"Understanding of ATP-lid conformational dynamics in the N-terminal domain of Hsp90 and its mutants by use of a computational biochemistry approach.","authors":"Keigo Gohda","doi":"10.1080/07391102.2025.2487202","DOIUrl":"https://doi.org/10.1080/07391102.2025.2487202","url":null,"abstract":"Chaperone Hsp90 regulates the activation and maturation of various protein, and is an attractive target for drug discovery. In catalytic cycle of Hsp90, ATP hydrolysis is a key event that drives structural changes, including the interchange of the dimeric Hsp90 structure between open and closed forms. For ATP hydrolysis, ATP-lid closure in the ATP-binding site from the up- to down-conformation is an indispensable co-ordinated structural change. However, the atomistic mechanism underlying lid closure remains unclear. In this study, a computational biochemistry approach was applied to wild-type apo and ATP-complex structures, and the lid-mutants A107N and T101I ATP-complex, to understand lid closure. A total of 15-μs molecular dynamic simulation, including the equilibration and production phases, was conducted for every structure starting from the lid up-conformation, but no lid-closures were observed. However, a very early event, i.e. a sign, of lid closure have been captured. In the simulations of wild-type and A107N ATP-complex structures, lid segment showed conformational fluctuations, and helix-7 (H7) segment in lid segment was unwound. This conformational instability of lid segment energetically weakened its interaction with facing region, suggesting the up-to-down transition was triggered by the instability of lid segment, particularly H7 segment. The interaction energy between lid segment and facing region was ranked in the order A107N > wild-type > T101I, which was correlated with experimental results such as the orders of ATP-hydrolytic activity and rapidity of conformational changes of lid segment, measured in ATP-spiking experiments by fluorescence resonance energy transfer method (i.e. A107N > wild-type > T101I).","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-12"},"PeriodicalIF":2.7,"publicationDate":"2025-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143795569","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Enhancing stability and catalytic activity of urate oxidase using natural deep eutectic solvent: insights from experimental and computational approaches. 利用天然深共熔溶剂增强尿酸氧化酶的稳定性和催化活性：来自实验和计算方法的见解。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-05 DOI: 10.1080/07391102.2025.2486444

Zahra Soltani-Nezhad, Maryam Zaboli, Mojtaba Mortazavi, Masoud Torkzadeh-Mahani

{"title":"Enhancing stability and catalytic activity of urate oxidase using natural deep eutectic solvent: insights from experimental and computational approaches.","authors":"Zahra Soltani-Nezhad, Maryam Zaboli, Mojtaba Mortazavi, Masoud Torkzadeh-Mahani","doi":"10.1080/07391102.2025.2486444","DOIUrl":"https://doi.org/10.1080/07391102.2025.2486444","url":null,"abstract":"This study investigated the impact of natural deep eutectic solvents (DES) based on sucrose, fructose and glycerol on the recombinant uricase enzyme. The plasmid recombinant pET-28a+ containing uricase coding sequence was extracted from the DH5α strain and transferred into the BL21 expration strain. Subsequently, overnight culture, induction with IPTG, and purification of the recombinant uricase using Ni-NTA affinity chromatography methods were carried out. The effect of DES containing sucrose, fructose and glycerol was assessed and 5% DES concentration verified for subsequent experiment. Thermodynamic parameters were analyzed using thermal inactivation and intrinsic fluorescence methods at temperatures of 35, 45, 55, and 65 °C. The results demonstrated lengthened enzyme half-life by approximately 61 min, higher activation energy and Tm, indicating improved thermal stability compared to the free enzyme. Kinetic tests revealed a reduction in the km value from 0.16 mM in the free enzyme to 0.09 mM in the treated enzyme, suggesting enhanced substrate binding affinity. Moreover, the Kcat/Km ratio, reflecting enzyme specificity towards the substrate, was enhanced. In the molecular dynamics simulation section, the root mean square deviation (RMSD), root mean square fluctuation (RMSF), and solvent accessible surface area (SASA) were analyzed. Lower RMSD and RMSF values indicate that the structure is more stable in the presence of the eutectic solvent compared to the free enzyme.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-18"},"PeriodicalIF":2.7,"publicationDate":"2025-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143788084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Analysis of the molecular interaction of mitragynine from kratom with human α₁-acid glycoprotein: biophysical and molecular modeling investigations. 克拉托姆中米特拉金碱与人α1-酸性糖蛋白的分子相互作用分析：生物物理和分子模型研究。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-03 DOI: 10.1080/07391102.2025.2483314

Khairul Azreena Bakar, Shevin Rizal Feroz

{"title":"Analysis of the molecular interaction of mitragynine from kratom with human α1-acid glycoprotein: biophysical and molecular modeling investigations.","authors":"Khairul Azreena Bakar, Shevin Rizal Feroz","doi":"10.1080/07391102.2025.2483314","DOIUrl":"https://doi.org/10.1080/07391102.2025.2483314","url":null,"abstract":"Mitragynine (MTG), the primary psychoactive alkaloid in Mitragyna speciosa (kratom), has garnered much attention for its therapeutic properties, which is attributed mainly to its selective action on opioid receptors. Despite its clinical potential, the molecular framework of its binding to plasma proteins remains incomplete. Specifically, no studies have thoroughly examined its interaction with α1-acid glycoprotein (AAG), a carrier protein in the circulatory system that influences drug disposition and bioavailability. Hence, this study aims to explore the binding dynamics between MTG and AAG using a combination of spectroscopic, calorimetric, microscopic, and computational methods. Based on isothermal titration calorimetric and fluorescence studies, an intermediate affinity for the MTG-AAG binding was determined (Ka ∼ 105 M-1). Despite evidence of microenvironmental changes around Trp residues, MTG binding did not disrupt the overall structural integrity of AAG. Thermodynamic analysis indicated that the MTG-AAG interaction was energetically favorable, and enthalpy driven mainly by hydrogen bonding and van der Waals forces, with negative entropy change suggesting a more ordered complex formation. Docking analysis showed MTG embedded more deeply within the central cavity of variant F1*S, enhancing complex stability, as opposed to binding near the cavity entrance in variant A. Molecular dynamics simulations supported the stable complexation of MTG with both AAG variants, with variant F1*S maintaining more structural compactness while variant A exhibited slight unfolding upon binding. These findings have clear significance on the potential therapeutic applications of kratom-derived drugs, especially those structurally related to MTG.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-17"},"PeriodicalIF":2.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772568","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Decoding the effect of temperatures on conformational stability and order of ligand unbound thermosensing adenine riboswitch using molecular dynamics simulation. 利用分子动力学模拟方法解码温度对配体非结合热敏腺嘌呤核糖开关构象稳定性和顺序的影响。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-03 DOI: 10.1080/07391102.2025.2484662

Soumi Das

{"title":"Decoding the effect of temperatures on conformational stability and order of ligand unbound thermosensing adenine riboswitch using molecular dynamics simulation.","authors":"Soumi Das","doi":"10.1080/07391102.2025.2484662","DOIUrl":"https://doi.org/10.1080/07391102.2025.2484662","url":null,"abstract":"The structure-function relationship of the riboswitch is governed mainly by two factors, ligand binding and temperature. Most of the experimental studies shed light on structural dynamics and gene regulation function of Adenine riboswitch from the aspect of ligand instead of temperature. Two unliganded Adenine riboswitch conformations (apoA and apoB) from the thermophile Vibrio vulnificus draw particular attention due to their diverse and polymorphic structures. Ligand-free apoB Adenine riboswitch conformation is not able to interact with the ligand whereas ligand-free apoA Adenine riboswitch conformation adopts ligand-receptive form. The interconversion between apoA and apoB conformation is temperature-dependent and thermodynamically controlled. Therefore Adenine riboswitch is called temperature sensing RNA. The molecular mechanism underlying the thermosensitivity of ligand free Adenine riboswitch is not well known. Hence an attempt is made to examine conformational stability and order of apoA with respect to apoB Adenine riboswitch aptamer computing RMSD, RMSF, RG, principal component analysis, hydrogen bonding interaction and conformational thermodynamics derived from all-atom molecular dynamics trajectories in the temperature range 283K-400K. The temperatures corresponding to the conformational stability and order of apoA adenine riboswitch with respect to apoB adenine riboswitch whole aptamer are shown in descending order 293K∼303K> 313K∼283K>373K>323K. Residue wise and domain wise changes in conformational free energy and entropy of conformational degrees of freedom like pseudo-torsion angle ƞ and θ reflect apoA exhibits pronounced conformational stability compared to apoB at temperatures 293K and 303K, whereas both forms reveal decreased stability at 323K and 400K and may be inactivated, highlighting their role as temperature sensors.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"1-14"},"PeriodicalIF":2.7,"publicationDate":"2025-04-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143772571","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Natural sapogenins as potential inhibitors of aquaporins for targeted cancer therapy: computational insights into binding and inhibition mechanism. 天然苷元作为用于癌症靶向治疗的潜在水囊蛋白抑制剂：结合和抑制机制的计算见解。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-01 Epub Date: 2024-01-04 DOI: 10.1080/07391102.2023.2299743

Modhi O Alotaibi, Nahaa M Alotaibi, Maha Abdullah Alwaili, Nawaf Alshammari, Mohd Adnan, Mitesh Patel

{"title":"Natural sapogenins as potential inhibitors of aquaporins for targeted cancer therapy: computational insights into binding and inhibition mechanism.","authors":"Modhi O Alotaibi, Nahaa M Alotaibi, Maha Abdullah Alwaili, Nawaf Alshammari, Mohd Adnan, Mitesh Patel","doi":"10.1080/07391102.2023.2299743","DOIUrl":"10.1080/07391102.2023.2299743","url":null,"abstract":"Aquaporins (AQPs) are membrane proteins that facilitate the transport of water and other small molecules across biological membranes. AQPs are involved in various physiological processes and pathological conditions, including cancer, making them as potential targets for anticancer therapy. However, the development of selective and effective inhibitors of AQPs remains a challenge. In this study, we explored the possibility of using natural sapogenins, a class of plant-derived aglycones of saponins with diverse biological activities, as potential inhibitors of AQPs. We performed molecular docking, dynamics simulation and binding energy calculation to investigate the binding and inhibition mechanism of 19 sapogenins against 13 AQPs (AQP0-AQP13) that are overexpressed in various cancers. Our results showed that out of 19 sapogenins, 8 (Diosgenin, Gitogenin, Tigogenin, Ruscogenin, Yamogenin, Hecogenin, Sarsasapogenin and Smilagenin) exhibited acceptable drug-like characteristics. These sapogenin also exhibited favourable binding affinities in the range of -7.6 to -13.4 kcal/mol, and interactions within the AQP binding sites. Furthermore, MD simulations provided insights into stability and dynamics of the sapogenin-AQP complexes. Most of the fluctuations in binding pocket were observed for AQP0-Gitogenin and AQP4-Diosgenin. However, remaining protein-ligand complex showed stable root mean square deviation (RMSD) plots, strong hydrogen bonding interactions, stable solvent-accessible surface area (SASA) values and minimum distance to the receptor. These observations suggest that natural sapogenin hold promise as novel inhibitors of AQPs, offering a basis for the development of innovative therapeutic agents for cancer treatment. However, further validation of the identified compounds through experiments is essential for translating these findings into therapeutic applications.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"3613-3634"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139087021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular docking and MD simulations reveal protease inhibitors block the catalytic residues in Prp8 intein of Aspergillus fumigatus: a potential target for antimycotics. 分子对接和 MD 模拟揭示蛋白酶抑制剂可阻断烟曲霉 Prp8 内蛋白的催化残基：抗霉菌药物的潜在靶标。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-01 Epub Date: 2023-12-27 DOI: 10.1080/07391102.2023.2298735

Sunita Panda, Madhusmita Rout, Sarbani Mishra, Jyotirmayee Turuk, Sanghamitra Pati, Budheswar Dehury

{"title":"Molecular docking and MD simulations reveal protease inhibitors block the catalytic residues in Prp8 intein of Aspergillus fumigatus: a potential target for antimycotics.","authors":"Sunita Panda, Madhusmita Rout, Sarbani Mishra, Jyotirmayee Turuk, Sanghamitra Pati, Budheswar Dehury","doi":"10.1080/07391102.2023.2298735","DOIUrl":"10.1080/07391102.2023.2298735","url":null,"abstract":"Resistance to azoles and amphotericin B especially in Aspergillus fumigatus is a growing concern towards the treatment of invasive fungal infection. At this critical juncture, intein splicing would be a productive, and innovative target to establish therapies against resistant strains. Intein splicing is the central event for the activation of host protein, essential for the growth and survival of various microorganisms including A. fumigatus. The splicing process is a four-step protease-like nucleophilic cascade. Thus, we hypothesise that protease inhibitors would successfully halt intein splicing and potentially restrict the growth of the aforementioned pathogen. Using Rosetta Fold and molecular dynamics simulations, we modelled Prp8 intein structure; resembling classic intein fold with horse shoe shaped splicing domain. To fully comprehend the active site of Afu Prp8 intein, C1, T62, H65, H818, N819 from intein sequences and S820, the first C-extein residue are selected. Molecular docking shows that two FDA-approved drugs, i.e. Lufotrelvir and Remdesivir triphosphate efficiently interact with Prp8 intein from the assortment of 212 protease inhibitors. MD simulation portrayed that Prp8 undergoes conformational change upon ligand binding, and inferred the molecular recognition and stability of the docked complexes. Per-residue decomposition analysis confirms the importance of F: block R802, V803, and Q807 binding pocket in intein splicing domain towards recognition of inhibitors, along with active site residues through strong hydrogen bonds and hydrophobic contacts. However, in vitro and in vivo assays are required to confirm the inhibitory action on Prp8 intein splicing; which may pave the way for the development of new antifungals for A. fumigatus.","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"3526-3541"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139040043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deciphering insights into the binding mechanism and plasticity of Telacebec with M. tuberculosis cytochrome bcc-aa3 supercomplex through an unbiased molecular dynamics simulation, free-energy analysis, and DFT study. 通过无偏见分子动力学模拟、自由能分析和 DFT 研究，破解 Telacebec 与结核杆菌细胞色素 bcc-aa3 超级复合物的结合机制和可塑性。

IF 2.7 3区生物学

Journal of Biomolecular Structure & Dynamics Pub Date : 2025-04-01 Epub Date: 2023-12-18 DOI: 10.1080/07391102.2023.2294833

Bedabrata Ray, Kuldeep K Roy

{"title":"Deciphering insights into the binding mechanism and plasticity of Telacebec with M. tuberculosis cytochrome bcc-aa3 supercomplex through an unbiased molecular dynamics simulation, free-energy analysis, and DFT study.","authors":"Bedabrata Ray, Kuldeep K Roy","doi":"10.1080/07391102.2023.2294833","DOIUrl":"10.1080/07391102.2023.2294833","url":null,"abstract":"The cytochrome bcc-aa3 supercomplex, a key component in the electron transport chain pathway involved in bacterial energy production and homeostasis, is a clinically validated target for tuberculosis (TB), leading to Telacebec (Q203). Telacebec is a potent candidate drug under Phase II clinical development for the treatment of drug-sensitive and drug-resistant TB. Recently, the cryo-electron microscopy structure of this supercomplex from Mycobacterium tuberculosis (Mtb) complexed with Q203 was resolved at 6.9 Å resolution (PDB ID: 7E1W). To understand the binding site (QP site) flexibility and Q203's stability at the QP site of the Mtb cytochrome bcc complex, we conducted molecular dynamics (MD) simulation and free energy analysis on this complex in an explicit hydrated lipid bilayer environment for 500 ns. Through this study, the persistence of a range of direct and indirect interactions was observed over the course of the simulation. The significance of the interactions with His375, Tyr161, Ala178, Ala179, Ile183, His355, Leu356, and Thr313 is underlined. Electrostatic energy was the primary source of the net binding free energy, regardless of the important interacting residues. The overall binding free energy for Q203 was -112.84 ± 7.73 kcal/mol, of which the electrostatic and lipophilic energy contributions were -116.31 ± 1.14 and -21.32 ± 2.35 kcal/mol, respectively. Meanwhile, DFT calculations were utilized to elucidate Q203's molecular properties. Overall, this study deciphers key insights into the cytochrome bcc-aa3 supercomplex with Q203 on the ground of molecular mechanics and quantum mechanics that may facilitate structure-based drug design and optimization for the discovery of the next-generation antitubercular drug(s).","PeriodicalId":15272,"journal":{"name":"Journal of Biomolecular Structure & Dynamics","volume":" ","pages":"2968-2981"},"PeriodicalIF":2.7,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138803730","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

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