Journal of Computer-Aided Molecular Design最新文献

{"title":"Multi-Omics Analysis of the virulence factors and designing of next-generation multi-epitopes Vaccines against Rickettsia prowazekii: a computer-aided vaccine designing approach","authors":"Fahad M. Alshabrmi","doi":"10.1007/s10822-025-00603-6","DOIUrl":"10.1007/s10822-025-00603-6","url":null,"abstract":"<div><p><i>Rickettsia</i> is a genus of bacteria that are obligate intracellular parasites and are responsible for the febrile diseases known collectively as Rickettsioses. The emergence of antibiotic resistance is an escalating concern and thus developing a vaccine against <i>Rickettsia</i> is of paramount importance due to the significant public health threat posed by these bacteria. Thus, we employed structural vaccinology guided by machine learning algorithms to explore the virulence landscape of <i>Rickettsia prowazekii</i> to design a multi-epitopes-based vaccine (MEVC) that is immunogenic and safe. From a pool of virulence factors, we shortlisted five targets including sca0, sca1, sca4, sca5 and tlyA that were classified as non-allergenic as well as antigenic. The immune epitopes mapping results shortlisted five CTL epitopes, five HTL (IFN+) epitopes and five B cell epitopes as the best choice to design a vaccine construct of 475 amino acids. Various parameters were used to validate the designed MEVC which involved prediction of physiochemical properties, modeling and validation of the 3D structure, interaction with the immune receptors such as TLR2 (Toll-like receptor) and TLR4. Moreover, all-atoms simulation and binding free energy (BFE) results revealed a stable and favorable dynamic properties determined by these complexes. Jcat revealed that the improved sequence exhibits a GC content of 48.14% and a CAI (Codon Adaptation Index) value of 1.0. We used a multi-dose criterion at different time intervals i.e., 1st, 84th and 170th day to understand the immune potential of our constructed vaccine. The results provide a comprehensive overview of immune factors that ensure effective antigen memory cells generation after each injection, as predicted by the in silico pipeline. However, limitations in current algorithms particularly their inability to fully account for HLA polymorphism and the lack of experimental and clinical validation remain major shortcomings of the study. These issues should be addressed in future research to support the development of a robust immune response against <i>Rickettsia</i> infections.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144135314","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}

{"title":"Targeting multiple pathways with virtual screening to identify the multi-target agent for Alzheimer’s disease treatment","authors":"Pitchayakarn Takomthong,&nbsp;Pornthip Waiwut,&nbsp;Chantana Boonyarat","doi":"10.1007/s10822-025-00602-7","DOIUrl":"10.1007/s10822-025-00602-7","url":null,"abstract":"<div><p>Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive memory loss, posing a significant risk, particularly within aging populations. Effective treatments to prevent or cure AD have remained elusive with current treatments only able to slow disease progression. Moreover, challenges in drug development for AD therapies are a complex pathology. A multi-target agent gained considerable interest over the single therapy in complex diseases, providing possible insights into therapeutic development by simultaneously targeting multiple pathological mechanisms. Virtual screening (VS) is a potent computational tool for identifying potential drug candidates from vast chemical databases, with subsequent molecular docking providing detailed insights into ligand-protein interactions. The ZINC database, housing millions of chemical compounds, serves as a valuable resource for screenings. Here, we conducted VS of compounds sourced from the ZINC database to identify potential multi-target AD agents. Through the VS analysis and subsequent in-vitro evaluations, our investigation identified one compound, ZINC006067856 (VS3), as a highly promising hit. This compound exhibited multifaceted actions against key AD pathological features, including cholinesterase inhibition, modulation of amyloid beta (Aβ) aggregation, and promotion of Aβ destabilization. Additionally, VS3 demonstrated neuroprotective effects against hydrogen peroxide-induced cell damage, further highlighting its potential as a comprehensive multi-targeted therapeutic agent for AD. Therefore, our findings suggested that VS3 held promise as a candidate for further preclinical and clinical investigations in the treatment of AD. Further elucidation of its mechanisms of action and comprehensive preclinical evaluations are required to assess its safety, efficacy, and therapeutic potential in improving AD clinical outcomes.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144084901","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}

{"title":"Theoretical investigation of AKT1 mutations in breast cancer: a computational approach to structural and functional insights","authors":"Balu Kamaraj,&nbsp;George Priya Doss C","doi":"10.1007/s10822-025-00601-8","DOIUrl":"10.1007/s10822-025-00601-8","url":null,"abstract":"<div><p>Breast cancer is a complex disease primarily driven by genetic mutations that disrupt crucial signaling pathways, with the <i>AKT1</i> gene playing a central role in its progression. This study explores the impact of AKT1 mutations using Whole Exome Sequencing (WES), bioinformatics, and computational modeling. Using WES, we identified and prioritized significant mutations in patient samples, specifically D3N, V337M, and D3N-E169G. Comprehensive sequence and structural analyses were conducted to understand how these mutations affect specific functional domains of the AKT1 protein. To investigate the molecular consequences, molecular docking studies were performed to assess the binding affinity of AKT1 mutations with MK2206, a known allosteric inhibitor of AKT1. The docking results revealed substantial differences in interaction energies, indicating impaired inhibitor binding due to these mutations. Additionally, molecular dynamics simulations over a 500-nanosecond trajectory provided detailed insights into the structural perturbations caused by these mutations. This integrated study, combining genomic and computational approaches, offers a comprehensive understanding of how AKT1 mutations contribute to BC pathogenesis. These findings enhance our knowledge of the molecular mechanisms underlying the disease and support the development of targeted therapies to address the altered behavior of mutated AKT1, advancing personalized treatment strategies for BC.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143925582","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}

{"title":"Decoding the multifunctional potential of ursolic acid: antioxidant, antiproliferative, molecular dynamics, and biodegradability evaluations of a mangrove-derived terpenoid","authors":"Anaikutti Parthiban,&nbsp;Veeraragavan Sachithanandam,&nbsp;Perumal Lalitha,&nbsp;Priyanka Adhikari,&nbsp;Santhiyagu Prakash,&nbsp;Ramasamy Ramasubburayan,&nbsp;Deepika Dhillon,&nbsp;Jayaraman Muthukumaran,&nbsp;Nambali Valsalan Vinithkumar,&nbsp;Rengurajan Sridhar,&nbsp;Ramachandran Purvaja","doi":"10.1007/s10822-025-00600-9","DOIUrl":"10.1007/s10822-025-00600-9","url":null,"abstract":"<div><p><i>Excoecaria agallocha</i> L, a mangrove plant widely used in traditional medication in India, was the focus of this study to evaluate its antioxidant, anticancer, structural, dynamic, and biodegradability properties of its bioactive compound, ursolic acid. This study, a sample (<i>E. agallocha</i>) collected from the tropical Islands ecosystem of South Andaman, India, represents the first report identifying Ursolic acid from the methanolic extract. The structure elucidation of the isolated bioactive compound was characterized using FT-IR, ¹H(Proton), ¹³C(Carbon) NMR spectroscopy, and HRMS. The antioxidant and anticancer activities were evaluated using the DPPH and MTT assay methods, respectively. The methanolic extract of <i>E. agallocha</i> demonstratedsignificantin vitro anticancer activity against Cervical (HeLa) and Breast (MDA-MB231) human cancer cell lines, with notable IC₅₀ values of 19.50 ± 0.41 µg/mL and 20.67 ± 0.14 µg/mL, respectively. It is highlighted that the ursolic acid’s anticancer activity was more potent, with IC₅₀ values of 3.5714 µg/mL against MDA-MB231 cells compared to the methanolic extract. The methanolic extract’s antioxidant properties with IC₅₀ values of 90.37 ± 0.41 and purified ursolic acid molecule exhibited promising IC₅₀ values of 7.59 ± 0.41 µg/mL. Gas Chromatography-Mass Spectrometry analysis of the methanolic extracts of <i>E. agallocha</i> revealed the presence of numerous pharmacologically bioactive compounds. In the in silico studies, molecular docking of two ligands, Ursolic acid and Obatoclax, with the Bcl-B protein demonstrated notable binding affinities, with <i>ΔG</i> values of -5.8 kcal/mol and − 6.6 kcal/mol, respectively. Ursolic acid’s binding affinity is comparable to Obatoclax’s, highlighting its potential as a viable anticancerous candidate for targeting Bcl-B protein. Assess the ligands’ impact on the protein’s stability, flexibility, compactness, folding properties, and solvent accessibility, MD simulations were performed. The MD simulation results revealed that the ligand-bound Bcl-B complexes exhibited significant structural stability, with moderate ligand-induced conformational changes observed in the target protein. Further, BIOWIN™ models indicated that the identified Ursolic Acid is biodegradable in an aerobic environment, underscoring its environmental compatibility. Deciphering the bioactivities of ursolic acid could uncover new therapeutic agents and enhance our understanding of its biodegradable environmental compatibility, revealing the source of already documented pharmacological compounds.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143883680","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}

{"title":"OPTUNA optimization for predicting chemical respiratory toxicity using ML models","authors":"Eman Shehab,&nbsp;Hamada Nayel,&nbsp;Mohamed Taha","doi":"10.1007/s10822-025-00597-1","DOIUrl":"10.1007/s10822-025-00597-1","url":null,"abstract":"<div><p>Predicting molecular toxicity is an important stage in the process of drug discovery. It is directly related to medical destiny and human health. This paper presents an enhanced model for chemical respiratory toxicity prediction. It used a combination of molecular descriptors and term frequency – inverse document frequency (TF-IDF) based models with different machine learning algorithms. To address class imbalance, SMOTE is applied. Appropriate hyper-parameter tuning is required to generate a better system with a classifier. So, we adjusted the hyper-parameters of various models and used the adjusted parameters to train the model. We tuned hyper-parameters using OPTUNA. Internal and external validation were used to confirm the models’ performance. According to the results, the model’s internal validation accuracy and AUC using the random forest approach were 88.6% and 93.2%. For external validation, the model’s accuracy value using random forest and Gradient Boosting Classifier were 92.2% with AUC 97%. Comparing these results with previous studies shows that our model performs better compared to them.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875320","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}

{"title":"Anticancer potential of novel benzothiazolyl piperidine-3-carboxamide derivatives as CDKs and VEGFR2 multi-target kinase inhibitors","authors":"Obaid Afzal,&nbsp;Ali Altharawi,&nbsp;Safar M. Alqahtani,&nbsp;Manal A. Alossaimi,&nbsp;Taibah Aldakhil,&nbsp;Abdulmalik S. A. Altamimi,&nbsp;Alhumaidi Alabbas,&nbsp;Mubarak A. Alamri","doi":"10.1007/s10822-025-00599-z","DOIUrl":"10.1007/s10822-025-00599-z","url":null,"abstract":"<div><p>The inhibition of cyclin-dependent kinases is a viable anticancer therapy due to their critical function in regulating cell cycle progression and transcription. The present study intended to design novel benzothiazolyl piperidine-3-carboxamide derivatives as multi-target CDKs and VEGFR2 inhibitor. Novel benzothiazolyl piperidine-3-carboxamide derivatives varying smaller and bulkier <i>N</i>-substitution at piperidine motif (<b>4a–f</b>) were designed based on the key structural features of SNS-032 (a CDK and VEGFR2 inhibitor). The compounds were subjected to extra-precision docking on seven CDKs and VEGFR2 kinase targets. The results revealed superior score/interaction of compounds with three CDKs (CDK2, CDK5, and CDK6) and VEGFR2, as compared to SNS-032. The best poses of <b>3</b>, <b>4b</b>, <b>4c</b> and SNS-032 were used in WaterMap study to analyze the hydration sites. MD simulations (100 ns) in the TIP3P water model for <b>4c</b> and SNS-032 were performed to analyze the trajectories for the deviation, fluctuations and intermolecular interaction, followed by the binding free energy calculations (MM-GBSA). All the compounds were synthesized and spectroscopically characterized by NMR, HPLC and LC–MS. In vitro CDKs (CDK2, CDK5, and CDK6) and VEGFR2 kinase inhibition assays revealed higher potency of compounds <b>3</b> (IC₅₀ 0.026 µM) and <b>4c</b> (IC₅₀ 0.048 µM) as compared to SNS-032 (IC₅₀ 0.052 µM) against CDK2, compounds <b>3</b> (IC₅₀ 0.315 µM), <b>4a</b> (IC₅₀ 0.248 µM), <b>4b</b> (IC₅₀ 0.276 µM), and <b>4c</b> (IC₅₀ 0.338 µM) as compared to SNS-032 (IC₅₀ 0.476 µM) against CDK5, compounds <b>3</b> (IC₅₀ 0.221 µM), <b>4a</b> (IC₅₀ 0.256 µM), <b>4b</b> (IC₅₀ 0.282 µM), <b>4c</b> (IC₅₀ 0.236 µM), and <b>4e</b> (IC₅₀ 0.274 µM) as compared to SNS-032 (IC₅₀ 0.365 µM) against CDK6, and comparable potency of compound <b>4b</b> (IC₅₀ 0.136 µM) with Sorafenib (IC₅₀ 0.114 µM) against VEGFR2. Furthermore, anticancer screening of compounds (<b>3</b> and <b>4a–f</b>) was performed against NCI (USA) 60 cancer cell lines by sulforhodamine B (SRB) colorimetric assay that revealed good to excellent anticancer activity.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143875310","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}

{"title":"Structure-based discovery of novel non-covalent small molecule inhibitors of USP30","authors":"Padmanabhan Anbazhagan,&nbsp;Jothi Anantharajan,&nbsp;Justina Fulwood,&nbsp;Choon Heng Low,&nbsp;Nithya Baburajendran,&nbsp;Klement Foo,&nbsp;Weijun Xu","doi":"10.1007/s10822-025-00596-2","DOIUrl":"10.1007/s10822-025-00596-2","url":null,"abstract":"<div><p>Ubiquitin-specific proteases (USPs) are crucial regulators of protein degradation pathways, influencing diverse cellular processes and disease mechanisms. Among them, USP30 plays a pivotal role in mitochondrial quality control and has been implicated in idiopathic pulmonary fibrosis (IPF), a chronic lung disease for which current therapies merely slow disease progression. The high flexibility of USP30’s catalytic site, coupled with its dependence on covalent interaction with the catalytic cysteine presents significant challenges in discovering suitable small molecule inhibitors. In this study, we identified three non-covalent small molecule inhibitors for USP30 using molecular modeling, X-ray crystallography, and virtual screening. These findings offer valuable insights and novel chemical starting points for further medicinal chemistry optimization.</p><h3>Graphical Abstract</h3><div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871344","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}

{"title":"Rational molecular design of novel class-III peptidic antagonists to competitively disrupt human PPARδ self-binding peptide","authors":"Yue Peng,&nbsp;Zilong Li,&nbsp;Yunyi Zhang,&nbsp;Haiyang Ye,&nbsp;Li Mei,&nbsp;Shuyong Shang,&nbsp;Peng Zhou","doi":"10.1007/s10822-025-00594-4","DOIUrl":"10.1007/s10822-025-00594-4","url":null,"abstract":"<div><p>Human peroxisome proliferator-activated receptor-δ (PPARδ) belongs to the nuclear receptor PPAR family that plays central roles in the regulation of glucose and lipid homeostasis and has also been implicated in cell proliferation, differentiation and inflammation. The PPARδ has a ligand-dependent transactivation function module located in the C-terminal helix 12 (H12) of its ligand-binding domain (LBD), which regulates the protein activation and inactivation by dynamically binding to and unbound from the H12-binding site (HBS) of PPARδ LBD domain, thus rendering the H12 as a so-called self-binding peptide (SBP). Currently, the existing PPARδ antagonists can be divided into two classes I and II in terms of their regulatory mechanism; the class-I antagonists competitively block natural agonists, while the class-II antagonists lock H12 out of the HBS site. In this study, class-III PPARδ antagonists were described, which directly target the HBS site and competitively disrupt the activation conformation of H12 in bound form. A self-inhibitory peptide termed HY12 with significant intrinstic disorder was derived from the H12 helical region, and we employed hydrocarbon stapling to constrain the HY12 peptide into a native-like, partially ordered helical conformation. It is confirmed that the stapling can effectively improve the peptide competition potency with native SBP for HBS site. The stapled peptides were considered as promising lead entities and can be used as the start to further develop the class-III peptidic antagonists of PPARδ.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143871409","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}

{"title":"MiR-146/TNF-α/IL-6/osteocalcin crosstalk in anti-rheumatic potential of Galleria mellonella hemolymph from computational molecular modeling to in-vivo validation","authors":"Sara M. Ahmed,&nbsp;Elham Ali,&nbsp;Amina R. Ali,&nbsp;Mona A. Mohamed,&nbsp;Hemmat Mansour Abdelhafez,&nbsp;Alya Mashaal","doi":"10.1007/s10822-025-00595-3","DOIUrl":"10.1007/s10822-025-00595-3","url":null,"abstract":"<div><p>Rheumatoid arthritis (RA) is an inflammatory autoimmune illness that persistently and recurrently affects joints. In RA, miR-146a functions as a key regulator, modulating inflammation by targeting and downregulating cytokines that promote inflammation, such as TNF-α and IL-6, whereas osteocalcin, a bone metabolism marker, plays a role in bone remodeling and joint health. The interplay between these molecules significantly influences RA progression and severity by balancing inflammation and bone integrity. Conventional antirheumatic drugs often cause varying levels of side effects. As sustainable development initiatives grow, insects are gaining interest as sustainable food sources and potential medicinal agents. Notably, the increasing <i>Galleria mellonella</i> (<i>G. mellonella</i>) population has raised concerns about the spread of honeybee viruses, affects bee products and food security, and drives economic losses in the therapeutic market. Accordingly, hemolymph has crucial defensive and immunological effects in insects and has recently been investigated as an immunomodulatory agent in parasitic in-vitro and in-vivo rat models. This work was designed to elucidate the potential immunomodulatory impact of <i>G. mellonella</i> hemolymph on the crosstalk between miR-146a, IL-6, TNF-α, and osteocalcin in the context of RA, utilizing both computational molecular modeling and in-vivo validation. Computer-aided molecular simulation for immune and RA mediators is applied through specific cell annotation, targeted pathways, and in-silico protein‒protein and gene‒gene interactions with a gene relative-tissue expression heatmap, which is based on gas chromatographic‒mass spectrometric analysis of hemolymph. Our study is the first to adapt a preliminary test to optimize hemolymph dosing and toxicity. The rats were subsequently divided into four groups: healthy control, Freund’s adjuvant-induced arthritis (utilized as a model that mimics human RA), methotrexate-treated arthritis, and hemolymph-treated arthritis groups. Our findings indicate that hemolymph contains valuable active compounds that have anti-inflammatory and antioxidant potential, increasing the impact of recovery on diseased joints in comparison with the arthritic and methotrexate groups. This is the first report investigating the maximum inhibition rate of <i>G. mellonella</i> hemolymph as an immunomodulatory and anti-inflammatory agent in an arthritic model.</p><h3>Graphical abstract</h3>\u0000<div><figure><div><div><picture><source><img></source></picture></div></div></figure></div></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://link.springer.com/content/pdf/10.1007/s10822-025-00595-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143861414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Deciphering the sequence-dependent unfolding pathways of an RNA pseudoknot with steered molecular dynamics","authors":"Akansha Pandit,&nbsp;Shubham Srivastava,&nbsp;Neeraj Kumar,&nbsp;Devesh M. Sawant","doi":"10.1007/s10822-025-00598-0","DOIUrl":"10.1007/s10822-025-00598-0","url":null,"abstract":"<div><p>Programmed ribosomal frameshifting in Simian retrovirus-1 (SRV-1) is sensitive to the mechanical properties of an RNA pseudoknot. Unravelling these mechanical intricacies via unfolding reveals fundamental insights into their structural dynamics. Using constant velocity steered molecular dynamics (CV-SMD) simulations, we explored the unfolding dynamics and the impact of mutations on the unfolding pathway of the pseudoknot. Except for A28C, A/U to C mutations that disrupt base triples between the loop 2 and stem 1 significantly weaken the pseudoknot and make it more susceptible to unfolding. Complementary mutations in 3 base pairs of the stem region (S1) enhanced its susceptibility to disruption except for Mut5 (S2). We quantitatively assessed the variations in unfolding pathways by analysing the opening of distinct Canonical (WC) and non-canonical (NWC) interactions, force-extension curves, and potential mean force profiles (as a guiding decision for planning mutations). These findings offer a quantified perspective, showcasing the potential of utilizing the unfolding pathways of RNA pseudoknots to explore the programmability of RNA structures. This insight proves valuable for designing RNA-PROTACS and RNA-aptamers, allowing for the assessment and manipulation of their biological folding/unfolding processes.</p></div>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":""},"PeriodicalIF":3.0,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143856473","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}