Molecular Diversity最新文献

{"title":"Pharmacoinformatics-based screening and construction of a neutralizing anti-SARS-CoV-2 camelidae nanobody drug conjugate.","authors":"Elora Kalita, Mamta Panda, Sarthak Dhar, Sanjana Mehrotra, Vijay Kumar Prajapati","doi":"10.1007/s11030-024-11086-2","DOIUrl":"https://doi.org/10.1007/s11030-024-11086-2","url":null,"abstract":"<p><p>Nanobodies or variable antigen-binding domains (V_HH) derived from heavy chain-only antibodies (HcAb) occurring in the Camelidae family offer certain superior physicochemical characteristics like enhanced stability, solubility, and low immunogenicity compared to conventional antibodies. Their efficient antigen-binding capabilities make them a preferred choice for next-generation small biologics. In the present work, we design an anti-SARS-CoV-2 bi-paratopic nanobody drug conjugate by screening a nanobody database. SAbDab-nano database was screened based on the physicochemical properties and SARS-CoV-2 binding affinity of the documented nanobodies. Molecular docking, computational modeling, in silico site-directed mutagenesis, and MD simulations were performed to construct an effective nanobody bi-paratope. The construct's physicochemical properties were assessed, and its structural integrity was validated through model energy refinement and quality assessment. The triple-mutant (N78Q K116N T123F) nanobody, based on the bioinformatics analysis, exhibited enhanced binding efficiency against its targets: SARS CoV-2 WT RB (- 353.3), NRP1 (- 376.5) and Omicron RBD (- 380.8), compared to the WT nanobody (SARS CoV-2 WT RBD = - 337.5, NRP1 = - 361.5, Omicron RBD = - 359.5). In silico evaluation also predicted that the construct would demonstrate efficient solubility, high thermostability (Tm 67.4 °C), low molecular weight of 29.36 KDa, and non-toxic, non-allergenic properties. Anti-SARS-CoV-2 neutralizing nanobody-based therapeutics, as demonstrated through this computational work, represents a promising alternative to traditional COVID-19 prophylaxis.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051163","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":"Quinoline and quinolone carboxamides: A review of anticancer activity with detailed structure-activity relationship analysis.","authors":"Neethu Mariam Thomas, Majed Alharbi, Venkanna Muripiti, Janardhan Banothu","doi":"10.1007/s11030-024-11092-4","DOIUrl":"10.1007/s11030-024-11092-4","url":null,"abstract":"<p><p>Quinoline is a highly privileged scaffold with significant pharmacological potential. Introducing a carbonyl group into the quinoline ring generates a quinolone ring, which exhibits promising biological properties. Incorporating a carboxamide linkage at different positions within the quinoline and quinolone frameworks has proven an effective strategy for enhancing pharmacological properties, particularly anticancer potency. Consequently, various scientific communities have explored quinoline and quinolone carboxamides for their anticancer activities, introducing modifications at key positions. This review article aims to compile the anticancer activity of various quinoline and quinolone carboxamide derivatives, accompanied by a detailed structure-activity relationship (SAR) analysis. It also categorizes the data into activities of isolated/fused quinoline and quinolone carboxamide derivatives, which were further subclassified based on the mechanisms of anticancer action. Among the numerous derivatives studied, compounds 8, 19, 31, 34, 40, 68, 108, 116, and 132 have emerged as the most potent anticancer agents, making them strong candidates for further drug design and development. The mechanisms underlying the anticancer activity of these potent compounds have been identified as inhibitors of topoisomerase (8, 19, 31, and 34), protein kinase (40, 108, and 116), human dihydroorotate dehydrogenase (68), and as a cannabinoid receptor 2 agonist (132). We anticipate this review will be valuable to researchers engaged in the structural design and development of quinoline and quinolone carboxamide-based anticancer drugs with high efficacy.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051248","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":"Bioinformatics and immunoinformatics approaches in the design of a multi-epitope vaccine targeting CTLA-4 for melanoma treatment.","authors":"Fatima Noor, Samiah Shahid, Muskan Fatima, Syed Zeeshan Haider, Zafer Saad Al Shehri, Faez Falah Alshehri, Abdur Rehman","doi":"10.1007/s11030-025-11108-7","DOIUrl":"https://doi.org/10.1007/s11030-025-11108-7","url":null,"abstract":"<p><p>Melanoma, a highly aggressive skin cancer, remains a significant cause of mortality despite advancements in therapeutic strategies. There is an urgent demand for developing vaccines that can elicit strong and comprehensive immune responses against this malignancy. Achieving this goal is crucial to enhance the efficacy of immunological defense mechanisms in combating this disease. This research provides a thorough examination of the design, optimization, and validation of a multi-epitope vaccine (MEV) construct. Using computational and in silico methods, the study specifically targets key immune receptors including MHC-I, MHC-I, and TLR4. The MEV construct was codon-optimized and effectively cloned into the E. coli pET-28a(+) vector to improve expression efficiency. To assess the stability and flexibility of the vaccine constructs in complex with their target receptors, molecular dynamics (MD) simulations were performed. The findings showed that the MHC-I-MEV complex demonstrated the greatest stability, with the MHC-II-MEV and TLR4-MEV complexes following instability. Immune simulation analyses revealed robust immune responses, evidenced by significant antibody production and the activation of cell mediated immune responses. These results highlight the MEV construct's potential as a versatile vaccine candidate, capable of eliciting strong and diverse immune responses. The integration of structural and energetic analyses, combined with immune simulation, provides a solid foundation for further experimental validation and therapeutic development.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051233","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":"Anti-cystitis glandularis action exerted by glycyrrhetinic acid: bioinformatics analysis and molecular validation.","authors":"Haiwei Hu, Yongbo Tang, Baotong Zhou, Shuangyan Chen, Jimin Su, Wei Zhong, Yuanyang Wei, Yipeng Huang, Bo Ge","doi":"10.1007/s11030-025-11105-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11105-w","url":null,"abstract":"<p><p>Cystitis glandularis (CG) is a chronic hyperplastic disorder of the bladder, and the available clinical drug therapy is insufficient currently. Glycyrrhetinic acid (GA), a bioactive compound extracted from the roots of Glycyrrhiza glabra, is found with beneficial actions, including anti-inflammatory and anti-oxidative effects. We previously reported that GA relieves CG symptoms in animal model, implying the potential application of GA to treat CG. However, the action mechanisms of GA against CG remain unclear. In this study, we aimed to identify the pivotal targets and therapeutic effects of GA through integrated bioinformatics analysis and experimental validation. Integrated bioinformatics analysis screened eleven potential therapeutic targets for GA against CG, and seven pivotal targets were identified subsequently. Enrichment gene analysis revealed GA exhibiting biological activities against CG via regulating multiple pharmacological targets and molecular pathways associated with inflammatory reaction and oxidative stress. Molecular docking computation revealed potent affinity and interaction between GA and prostaglandin-endoperoxide synthase 2 (PTGS2) and mucin 1 (MUC1) proteins in CG. To validate biochemically, increased mRNA and protein expressions of PTGS2 and MUC1 were observed in human CG samples. Compared to CG mice, GA-treated CG mice exhibited reduced inflammatory cytokine contents and downregulated PTGS2 and MUC1 mRNA and protein levels. These integrated findings suggest the potential therapeutic effects of GA against CG via the regulation of targeting genes and pathways. However, further studies are necessary to perform and facilitate the clinical application of GA for treating CG.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051231","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":"Inhibition of amyloid-beta aggregation by phenyl butyric acid analogs and bile acids: a comprehensive in silico study.","authors":"Rimaljot Singh, Navpreet Kaur, Shiwani Sharma, Neelima Dhingra, Tanzeer Kaur","doi":"10.1007/s11030-024-11101-6","DOIUrl":"https://doi.org/10.1007/s11030-024-11101-6","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a degenerative neurological disorder defined by the formation of β-amyloid (Aβ) plaques and neurofibrillary tangles within the brain. Current pharmacological treatments for AD only provide symptomatic relief, and there is a lack of definitive disease-modifying therapies. Chemical chaperones, such as 4-Phenylbutyric acid (4PBA) and Tauroursodeoxycholic acid, have shown neuroprotective effects in animal and cell culture models. However, their therapeutic application is limited due to low bioavailability and poor ability to cross the blood-brain barrier. The study aims to design and identify novel derivatives of 4PBA analogs & bile acids using computational molecular docking, ADME/pharmacokinetic predictions, and molecular dynamic (MD) simulations to develop potential anti-aggregation compounds targeting Aβ, a key player in AD pathology. A comprehensive library of 25,802 derivatives was created using 3PPA, 3MPP, 5PVA, IPA, and bile acid scaffolds, which were examined for their pharmacokinetic characteristics and binding affinities with the Aβ protein. Molecular docking and ADME predictions revealed IPA-1 and DCA-1 as leading candidates due to their robust binding interactions with the Aβ protein, along with minimal toxicity, high solubility, and good absorption profiles. Further, MD analysis over an extended period at 100 ns confirmed the better stability of IPA-1 and DCA-1 during interaction with the protein. These findings highlight promising drug candidates, necessitating further validation through cell and animal studies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143051235","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":"Advances in cyclotide research: bioactivity to cyclotide-based therapeutics.","authors":"Ankita Grover, Sawraj Singh, Sonal Sindhu, Amit Lath, Sanjay Kumar","doi":"10.1007/s11030-025-11113-w","DOIUrl":"https://doi.org/10.1007/s11030-025-11113-w","url":null,"abstract":"<p><p>Cyclotides are a class of plant-derived cyclic peptides having a distinctive structure with a cyclic cystine knot (CCK) motif. They are stable molecules that naturally play a role in plant defense. Till date, more than 750 cyclotides have been reported among diverse plant taxa belonging to Cucurbitaceae, Violaceae, Rubiaceae, Solanaceae, and Fabaceae. These native cyclotides exhibit several bioactivities, such as anti-bacterial, anti-HIV, anti-fungal, pesticidal, cytotoxic, and hemolytic activities which have immense significance in agriculture and therapeutics. The general mode of action of cyclotides is related to their structure, where their hydrophobic face penetrates the cell membrane and disrupts it to exhibit anti-microbial, cytotoxic, or hemolytic activities. Thus, the structure-activity relationship is of significance in cyclotides. Further, owing to their, small size, stability, and potential to interact and cross the membrane barrier of cells, they make promising choices for developing peptide-based biologics. However, challenges, such as production complexity, pharmacokinetic limitations, and off-target effects hinder their development. Advancements in cyclotide engineering, such as peptide grafting, ligand conjugation, and nanocarrier integration, heterologous production along with computational design optimization, can help overcome these challenges. Given the potential of these cyclic peptides, the present review focuses on the diversity, bioactivities, and structure-activity relationships of cyclotides, and advancements in cyclotides engineering emphasizing their unique attributes for diverse medical and biotechnological applications.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035844","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":"Inhibitors of NADH-O-methylquinone compound a class of antitubercular drugs.","authors":"Dongzi Lin, Cheng Xu, Changyou Gan, Bihua Ou, Fengxian Luo, Zhigang She, Lei Zhou, Zhenhua Chen","doi":"10.1007/s11030-025-11117-6","DOIUrl":"https://doi.org/10.1007/s11030-025-11117-6","url":null,"abstract":"<p><p>Disruption of the mycobacterial redox homeostasis leads to irreversible stress induction and cell death. Hydroquinone scaffolds, as a new type of redox cycling anti-tuberculosis chemotypes, exhibit potent bactericidal activity against non-replicating, nutrient-deprived phenotypically drug-resistant bacteria. Evidences from microbiological, biochemical, and genetic studies indicate that the redox-driven mode of action relies on the reduction of quinones by type II NADH dehydrogenase (NDH2), generating reactive oxygen species (ROS) of bactericidal level. This study demonstrates that (S)-Peniphenone D possesses significant resistance to Mycobacterium marinum (M. marinum) infection, as it enables redox cycling within M. marinum cells, ROS production, and reduction of intracellular NADH levels. The results suggest that hydroquinone compounds, due to their distinctive biological activities, could serve as novel sources for antibacterial drugs, particularly in developing scaffolds for new anti-tuberculosis agents.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035788","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":"A multiscale molecular structural neural network for molecular property prediction.","authors":"Zhiwei Shi, Miao Ma, Hanyang Ning, Bo Yang, Jingshuang Dang","doi":"10.1007/s11030-024-11100-7","DOIUrl":"https://doi.org/10.1007/s11030-024-11100-7","url":null,"abstract":"<p><p>Molecular Property Prediction (MPP) is a fundamental task in important research fields such as chemistry, materials, biology, and medicine, where traditional computational chemistry methods based on quantum mechanics often consume substantial time and computing power. In recent years, machine learning has been increasingly used in computational chemistry, in which graph neural networks have shown good performance in molecular property prediction tasks, but they have some limitations in terms of generalizability, interpretability, and certainty. In order to address the above challenges, a Multiscale Molecular Structural Neural Network (MMSNet) is proposed in this paper, which obtains rich multiscale molecular representations through the information fusion between bonded and non-bonded \"message passing\" structures at the atomic scale and spatial feature information \"encoder-decoder\" structures at the molecular scale; a multi-level attention mechanism is introduced on the basis of theoretical analysis of molecular mechanics in order to enhance the model's interpretability; the prediction results of MMSNet are used as label values and clustered in the molecular library by the K-NN (K-Nearest Neighbors) algorithm to reverse match the spatial structure of the molecules, and the certainty of the model is quantified by comparing virtual screening results across different K-values. Experimental results in the authoritative small molecule dataset QM9 and the macromolecular protein database PDBbind demonstrate that MMSNet has optimal prediction accuracy, model complexity, and generalizability compared with more than ten existing state-of-the-art (SOTA) models in a variety of different types of prediction tasks; it has a great potential for downstream tasks such as chemical research, drug discovery, and material design.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143035840","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 antifungal activity of arecoline derivatives containing amino acid fragments.","authors":"Xianwu Liu, Jianwen Zhang, Zefang Qin, Chengcheng Zhang, Huaxin Liu, Ting Zhou, Lanying Wang, Yanping Luo, Zhigang Zeng","doi":"10.1007/s11030-024-11102-5","DOIUrl":"https://doi.org/10.1007/s11030-024-11102-5","url":null,"abstract":"<p><p>A series of new arecoline derivatives containing amino acid fragments were synthesized, and their fungicidal activities were investigated. All synthesized compounds were characterized by ¹H NMR, ¹³CNMR, and HRMS. Preliminary bioactivity assays demonstrated that Compounds 3k, 3n, 3p, 3q, 3r, and 3s exhibited significant antifungal activity against Botryosphaeria cactivora, Botryosphaeria dothidea, and Fusarium pseudograminearum at a concentration of 100 μg/mL. Among them, Compound 3s displayed the highest inhibitory activity against Botryosphaeria dothidea (96.63%), surpassing the commercial fungicide chlorothalonil (91.30%). To explore the underlying mechanisms of the compounds, preliminary investigations into the antifungal mechanism involved molecular docking study, scanning electron microscopy and fluorescence microscopy observations, assessments of membrane permeability, and measurements of malondialdehyde content were carried out, respectively. The findings demonstrated that Compound 3s effectively inhibits fungal hyphal growth by compromising the integrity of the hyphal cell membrane. These results indicate that arecoline derivatives containing amino acid benzyl esters have potential as promising fungicides.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143031799","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 biological evaluation of rationally designed pyrazoles as insecticidal agents.","authors":"Aroog Fatima, Samina Aslam, Sara Janiad, Shah Faisal, Ali Irfan, Javed Iqbal, Gamal A Shazly, Ansa Madeeha Zafar, Aqeela Shaheen, Sobia Noreen, Emilio Mateev, Yousef A Bin Jardan","doi":"10.1007/s11030-024-11094-2","DOIUrl":"https://doi.org/10.1007/s11030-024-11094-2","url":null,"abstract":"<p><p>The current research focused on the synthesis of two series of pyrazole derivatives and evaluation of their insecticidal effectiveness. In the first series, seven pyrazole Schiff bases 3a-g were successfully synthesized with yields (79-95%) by condensing phenylfuran-2-carbaldehyde with substituted pyrazole rings. In the second series, eleven amino acid-pyrazole conjugates 6a-k were synthesized utilizing acetic acid, sulfuric acid, morpholine, and EDC. HCl achieving yields of 59% to 94%. The synthesized compounds were assessed for their chemotherapeutic efficacy against locusts and termites by calculating LC₅₀ values, thereby determining their potential as anti-termite and anti-locust agents. Among the eighteen synthesized pyrazole compounds, the Schiff base pyrazole molecules 3f (LC₅₀ = 0.001 μg/mL) and 3d (LC₅₀ = 0.006 μg/mL) demonstrated excellent anti-termite activity compared to the reference drug fipronil (LC₅₀ = 0.038 μg/mL). Pyrazole derivative 6 h with LC₅₀ = 47.68 μg/mL exhibited superior anti-locust activity than the reference drug fipronil (LC₅₀ = 63.09 μg/mL). Additionally, compound 3b, containing NO₂ functionality at the meta position, exhibited notable and significant anti-locust activity with an LC₅₀ values of 100.00 μg/mL. However, the highest mortality was caused by the glycine conjugate of fipronil 6 h of the 2nd series with an LC₅₀ value of 47.68 μg/mL, which also proved to be a potent anti-locust agent. This study explores the efficacy of biologically active pyrazole structures as potential insecticidal agents through a combination of virtual molecular docking analysis and biological experimental investigations. The results demonstrate a strong correlation between the computational predictions and experimental outcomes, suggesting that the pyrazole derivatives exhibit significant insecticidal properties. The findings highlight the potential of these compounds in the development of innovative insecticides, paving the way for future research in pest control strategies.</p>","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143027666","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}