Abdulaziz Alamri, Saeedah Almutairi, Salman Al Rokayan, Mohamed Y Zaky, Mostafa A Abdel-Maksoud, Israr Fatima
{"title":"Immunoinformatics-driven design of a multi-epitope vaccine for effective protection against Machupo virus.","authors":"Abdulaziz Alamri, Saeedah Almutairi, Salman Al Rokayan, Mohamed Y Zaky, Mostafa A Abdel-Maksoud, Israr Fatima","doi":"10.1007/s11030-025-11249-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11249-9","url":null,"abstract":"<p><p>The Arenaviridae family of viruses includes the Machupo virus (MACV), which is associated with the potentially fatal Bolivian hemorrhagic fever, a disease with a mortality rate of 15%-30% depending on the speed of diagnosis and the availability of health facilities. To date, there is no licensed vaccine available for MACV, highlighting the need for a preventive measure. In this work, we use immunoinformatics approaches to create a multi-epitope vaccine based on the most dominant MACV proteins. For constructational epitopes, we selected glycoprotein precurssor (GP), nucleoprotein (NP), RNA-dependant RNA polymerase (L), and Zinc-binding RING finger protein (Z) from garner the proteins essential for replicating and invading a host cell. Using in silico prediction methods, a total of thirteen T-cell epitopes (seven MHC class I and six MHC class II binders) and eight B-cell epitopes were identified as having the greatest potential to elicit strong and broad-spectrum immune responses. These selected epitopes were validated in silico to ensure the highest degree of immunogenicity and no allergenic or toxic effects. To increase the potential of the vaccine to elicit an immune response, the 50S ribosomal protein L7/L12 was added as an adjuvant. The analysis of population coverage indicated that the epitopes could provide immunological protection to nearly 98.04% of the world population. The theoretical vaccine design included 3D modeling and simulation of docking to immunoreceptors like Toll-like receptor 4 (TLR4) and MHC molecules, which confirmed their stable and high-affinity binding interactions. The results from in silico simulations of the immune response also showed abundant production of antibodies and strong engagement of various T-cell subsets. In summary, this study proposes a multi-epitope Machupo virus vaccine candidate that can be tested in the lab to evaluate its effectiveness as a preventative measure for Bolivian hemorrhagic fever.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144641369","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Synthesis and multi-target evaluation of 2-(2-phenylethyl)/2,3-styrylchromone derivatives as potential anti-Alzheimer's disease agents.","authors":"JiaHao Lu, YingQI Qiu, ChenHao Zhao, Ai-Qun Wu, Haiou Jiang, Li-Qun Shen","doi":"10.1007/s11030-025-11284-6","DOIUrl":"https://doi.org/10.1007/s11030-025-11284-6","url":null,"abstract":"<p><p>A series of novel 2-(2-phenylethyl)chromone and 2/3-styrylchromone derivatives (A1-A16, B1-B43) were designed, synthesized, and systematically evaluated for their multi-target activities against key pathological factors of Alzheimer's disease (AD). In vitro studies demonstrated that compound B22 exhibited potent and selective acetylcholinesterase (AChE) inhibition (IC₅₀ = 2.52 ± 1.11 μM) with negligible activity against butyrylcholinesterase (BuChE) (IC₅₀ > 500 μM), along with strong monoamine oxidase-B (MAO-B) inhibition (93.6% inhibition at 1 μM). Thioflavin T (ThT) fluorescence assays revealed that B18 and B22 effectively inhibited the aggregation of both Aβ40/42 peptides (IC₅₀ = 1.44 and 1.00 μM, respectively) and Tau fibrillization (IC₅₀ = 2.61 and 3.32 μM), while promoting the disaggregation of pre-formed amyloid fibrils. Molecular docking and molecular dynamics (MD) simulations indicated that B22 exhibited favorable binding affinities (ΔG ≈ - 7.3 kcal/mol) and stable interactions within the AChE active site. Furthermore, B22 significantly attenuated reactive oxygen species (ROS) levels (by up to 89.5%) and rescued Aβ-induced cytotoxicity in SHSY5Y cells, restoring cell viability to 85.7% at 20 μM. Collectively, these results highlight chromone-based scaffolds, particularly compound B22, as promising multifunctional candidates for the development of disease-modifying therapeutics targeting AD.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ali Al-Samydai, Farah Al-Mamoori, Amal Mayyas, Amjad Ibrahim Oraibi, Hany Akeel Al-Hussaniy, Ali Almukram, Faiyaz Shakeel
{"title":"Structure-based cheminformatics and molecular dynamics profiling of potential SIRT6 inhibitors.","authors":"Ali Al-Samydai, Farah Al-Mamoori, Amal Mayyas, Amjad Ibrahim Oraibi, Hany Akeel Al-Hussaniy, Ali Almukram, Faiyaz Shakeel","doi":"10.1007/s11030-025-11285-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11285-5","url":null,"abstract":"<p><p>Sirtuin-6 (SIRT6) is a NAD+-dependent deacetylase that maintains genome stability, metabolic regulation, and cellular stress responses, making it an attractive target for therapeutic intervention in metabolic and age-related diseases. Despite its biological importance, the identification of potent SIRT6 modulators remains limited. In this study, we applied an integrative computational approach combining cheminformatics, network pharmacology, molecular docking, and molecular dynamics simulations to explore new inhibitory candidates targeting SIRT6. A curated dataset of 78 CHEMBL compounds was used to develop robust multi-fingerprint QSAR models using Random Forest algorithms, validated through Y-randomization, external testing, and applicability domain analysis. Network pharmacology analysis revealed functional associations between SIRT6 and key regulatory proteins such as NAMPT, CD38, and HIF1A, highlighting its involvement in NAD⁺ biosynthesis and cellular stress pathways. Molecular docking identified CHEMBL50 (Quercetin) and CHEMBL4217987 as top candidates with favorable interactions at the SIRT6 catalytic site. These complexes were further evaluated through 200 ns MD simulations. Binding stability was confirmed using MM-GBSA free energy calculations, dynamic cross-correlation matrix (DCCM), and principal component analysis (PCA), demonstrating energetically favorable and stable protein-ligand interactions. Overall, this study offers a predictive and mechanistic framework for SIRT6 inhibitor discovery and provides lead scaffolds for further optimization and experimental validation.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144615763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Vincent A Obakachi, Krishna K Govender, Penny P Govender
{"title":"A dynamic scapping workflow for RTK domains: computational modeling of natural products as dual modulators of EGFR and VEGFR signaling in breast cancer.","authors":"Vincent A Obakachi, Krishna K Govender, Penny P Govender","doi":"10.1007/s11030-025-11263-x","DOIUrl":"https://doi.org/10.1007/s11030-025-11263-x","url":null,"abstract":"<p><p>Breast cancer, a major global health challenge, is driven by aberrant receptor tyrosine kinase (RTK) signaling via epidermal growth factor receptor (EGFR) and vascular endothelial growth factor receptor (VEGFR). This study employs a \"Dynamic Scapping\" workflow, integrating molecular docking, 500 ns molecular dynamics (MD) simulations, and MM/GBSA binding free energy calculations to identify natural products with potential for dual binding to EGFR (PDB: 1M17) and VEGFR (PDB: 3VHE). From ~ 20,000 natural products, virtual screening shortlisted 13 EGFR and 12 VEGFR hits, with Digitonin, Cyclamin, Vicenin-2, Glucosylorientin, and Nicotiflorin selected for EGFR, and Quercetagetin, Silychristin, Quercetin, Scutellarein, and Isorhamnetin for VEGFR, alongside references (Erlotinib, Pyrrolopyrimidine). MD simulations, conducted as single trajectories per system, revealed stable complexes (RMSD: 1.73-2.92 Å), with Digitonin, Cyclamin, and Silychristin showing binding energies (ΔG<sub>bind</sub>: - 84.29, - 81.47, - 63.33 kcal/mol) compared to references (Erlotinib: - 43.32 kcal/mol and Pyrrolopyrimidine: - 61.63 kcal/mol). Dynamic analyses (DCCM, PCA) indicated restricted motions, while per-residue decomposition highlighted interactions with Met769 (EGFR) and Cys919 (VEGFR). The MM/GBSA calculations excluded the entropy term, potentially affecting absolute binding energies but supporting relative ranking. These computational findings suggest Digitonin, Cyclamin, and Silychristin as candidates with the potential for dual binding to EGFR and VEGFR, addressing the need for accessible treatments globally and in regions like South Africa with high incidence rates. Experimental validation is essential to confirm their functional dual modulation and inhibitory potency for breast cancer therapy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144606983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"Exploring graph-based models for predicting active compounds against triple-negative breast cancer.","authors":"Hridoy Jyoti Mahanta, Amarjeet Boruah, Bikram Phukan, Hillul Chutia, Pankaj Bharali, Selvaraman Nagamani","doi":"10.1007/s11030-025-11283-7","DOIUrl":"https://doi.org/10.1007/s11030-025-11283-7","url":null,"abstract":"<p><p>Breast cancer is among the most dominant and rapidly rising cancers, both in India and around the world. Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, distinguished by the absence of HER2, progesterone, and estrogen receptor expressions. This absence limits treatment options, emphasizing the urgent need to discover or design new drug candidates for TNBC. Integrating artificial intelligence and machine learning in computational modeling, has significantly accelerated the analysis of large-scale biological data and improved the prediction of therapeutic outcomes. In this study, we curated a data set of 756 mutant-type compounds from three cell lines and developed four graph-based models to predict active compounds against TNBC. Validated using stratified nested tenfold cross-validation and optimized with the Optuna framework, the models achieved predictive accuracy with AUC values of 0.65-0.82, with the MPNN model outperforming all the others. Furthermore, key structural fragments associated with cell inhibition and model predictions were identified and interpreted using several explainability techniques. Validation with an external set of FDA-approved drugs demonstrated prediction accuracies ranging from 66% to 97%, highlighting the robustness of the models in identifying compounds with potential inhibitory activity against TNBC cells.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590194","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shakshi Shah, Ankita Sharma, Kanika Choudhary, Rakesh Kumar, Vikram Singh, Amit Kumar Sharma, Sunil Kumar, Dixit Sharma
{"title":"Exploring OmpA of Orientia tsutsugamushi to design novel multi-epitope vaccine against scrub typhus: an immunoinformatics approach.","authors":"Shakshi Shah, Ankita Sharma, Kanika Choudhary, Rakesh Kumar, Vikram Singh, Amit Kumar Sharma, Sunil Kumar, Dixit Sharma","doi":"10.1007/s11030-025-11236-0","DOIUrl":"https://doi.org/10.1007/s11030-025-11236-0","url":null,"abstract":"<p><p>Scrub typhus is a commonly neglected infectious febrile illness caused by an obligate intracellular bacterium known as Orientia tsutsugamushi. It is a major health problem, affecting one million people annually, and poses threat to one billion people worldwide. There is always the escalating threat posed by the development of antibiotic resistance in the forthcoming future which emphasizes on urgency of the development of vaccine against Orientia tsutsugamushi. Despite eight decades of research and development, currently there is no viable vaccine available against scrub typhus. Outer membrane protein A (OmpA) is highly conserved and immunogenic across 51 geographically diverse isolates of Orientia tsutsugamishi. The multi-epitope vaccine was constructed by integrating four B-cell, four MHC-I, and four MHC-II epitopes linked together using specific linkers. The cholera enterotoxin subunit B is linked with the vaccine construct at N-terminal as an adjuvant. The constructed vaccine is 329 amino acid long, highly antigenic, non-allergen, non-toxic, soluble and has 36.3 kDa molecular weight. The molecular docking of vaccine construct with TLR receptors showed strong binding affinity. The interactions among vaccine and TLR receptors were analyzed using PDBsum. The in silico immune simulation of constructed vaccine showed ability to trigger immune response as shown by augmentation in T-cell and B-cell population. The current study provides the way forward for controlling the febrile disease scrub typhus.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Maryam Salehi, Anna Sedaghat, Maryam Bayanati, Mohammad Ismail Mahboubi Rabbani, Elham Rezaee, Sayyed Abbas Tabatabai
{"title":"Novel dual inhibitor targeting FAAH and sEH: Design, synthesis, and in-vitro evaluation of oxadiazole analogues.","authors":"Maryam Salehi, Anna Sedaghat, Maryam Bayanati, Mohammad Ismail Mahboubi Rabbani, Elham Rezaee, Sayyed Abbas Tabatabai","doi":"10.1007/s11030-025-11267-7","DOIUrl":"https://doi.org/10.1007/s11030-025-11267-7","url":null,"abstract":"<p><p>Fatty acid amide hydrolase (FAAH) enzyme, as a potential therapeutic target for the treatment of pain and inflammation, is responsible for decomposing fatty acid amides like endocannabinoids. One attractive technique for increasing the efficacy of FAAH inhibitors is to generate antinociception and anti-inflammatory effects via another route, such as soluble epoxide hydrolase (sEH) inhibition, at the same time. In this study, two series of structures bearing oxadiazole rings as dual inhibitors of FAAH/sEH were designed, synthesized, and biologically evaluated. Most compounds showed an excellent affinity towards the active sites of both enzymes compared to the standard ligands of JZL-195 and AUDA. Among all the synthesized compounds, compound 7f was a more effective inhibitor with IC<sub>50</sub> values of 1.2 nM and 18 nM on FAAH and sEH enzymes, respectively. The results of the in-vitro evaluation were significantly consistent with the docking results.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574642","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Adrija Banerjee, Gatta K R S Naresh, Lalitha Guruprasad
{"title":"Design of inhibitors to Klebsiella pneumoniae aspartate semialdehyde dehydrogenase towards hospital-acquired infections.","authors":"Adrija Banerjee, Gatta K R S Naresh, Lalitha Guruprasad","doi":"10.1007/s11030-025-11277-5","DOIUrl":"https://doi.org/10.1007/s11030-025-11277-5","url":null,"abstract":"<p><p>Hospital-acquired infections (HAIs) caused by viral, bacterial, and fungal pathogens have resulted in numerous deaths all over the world. Klebsiella pneumoniae (Kp) is a drug-resistant Gram-negative bacterium responsible for HAIs. Aspartate β-semialdehyde dehydrogenase (ASADH) enzyme is crucial for the survival of Kp since it is involved in the biosynthetic pathway responsible for the production of essential amino acids and important metabolites. This pathway is absent in mammals and hence design of inhibitors for Kp ASADH becomes a good strategy for the treatment of HAIs. In this study, computational methodologies were employed to design inhibitors targeting Kp ASADH. Key active site residues were identified through the analysis of binding interactions with two established lead compounds, 4-nitro-2-phosphonobenzoic acid and (S)-methyl cysteine sulfoxide. A virtual screening of compounds from the NCI Diversity Database was conducted using molecular docking within the active site in the presence of coenzyme NADPH. Drug-like properties of the identified hit compounds were subsequently evaluated. These molecules were further validated using molecular dynamics simulations to assess their structural stability. The finalized hit compounds underwent additional stability assessments through normal mode analysis, mechanical stiffness evaluation, principal component analysis, and binding energy calculations using MM/GBSA. ADMET profiles of the final compounds were examined.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Juan Huang, Xiaoyan Yang, Qiuqian Huang, Yangyang Gao, Pradeepa C G Bandaranayake, Wishwajith Kandegama, Charles R Ashby, Yawen Dong, Zhenchao Wang, Ge-Fei Hao
{"title":"Unraveling the secrets of novel PROTACs to improve degradation efficacy.","authors":"Juan Huang, Xiaoyan Yang, Qiuqian Huang, Yangyang Gao, Pradeepa C G Bandaranayake, Wishwajith Kandegama, Charles R Ashby, Yawen Dong, Zhenchao Wang, Ge-Fei Hao","doi":"10.1007/s11030-025-11273-9","DOIUrl":"https://doi.org/10.1007/s11030-025-11273-9","url":null,"abstract":"<p><p>Proteolysis targeting chimera (PROTAC) represents a crucial approach for overcoming various limitations associated with traditional inhibitors, particularly in targeting \"undruggable\" proteins and overcoming the resistance of targets. The degradation efficiency of PROTAC is fundamental to its pharmacological activity. Improving PROTAC's degradation efficiency mainly focuses on small molecule design, exploring new mechanisms, and optimizing delivery strategies. However, there is a lack of comprehensive understanding regarding how novel PROTACs enhance degradation efficacy. Here, a comprehensive exploration of novel PROTACs has been conducted to reveal the mechanisms of enhanced degradation efficiency through an in-depth analysis of tremendous existing studies. Firstly, we describe the variables influencing PROTAC's degradation activity. Secondly, a complete analysis is launched between novel PROTACs and their traditional counterparts, elucidating the reasons for the improved degradation efficacy of newer forms. Finally, the successful cases are leveraged to verify the theoretical foundation underlying enhanced degradation efficacy. We believe this work is anticipated to offer new perspectives for the design and guide the creation of potent PROTACs.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144566958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}