Journal of Computer-Aided Molecular Design最新文献

{"title":"Protein-ligand co-design: a case for improving binding affinity between type II NADH:quinone oxidoreductase and quinones.","authors":"Vladimir Porokhin, Anne M Brown, Soha Hassoun","doi":"10.1007/s10822-025-00613-4","DOIUrl":"https://doi.org/10.1007/s10822-025-00613-4","url":null,"abstract":"<p><p>Biological engineering aims to enhance biological systems by designing proteins with improved catalytic properties or ligands with enhanced function. Typically, applications permit designing proteins, e.g., an enzyme in a biodegradation reaction, or ligands e.g., a drug for a target receptor, but not both. Yet, some applications can benefit from a more flexible approach where both the protein and ligand can be designed or modified together to enhance a desired property. To meet the need for this co-design capability, we introduce a novel co-design paradigm and demonstrate its application to Ndh2-quinone pairings to enhance their binding affinity. Ndh2, type-II NADH dehydrogenase, is an enzyme found in certain bacteria that facilitates extracellular electron transfer (EET) when interacting with exogenous quinone mediators. This interaction leads to the generation of a detectable electric current that can be used for biosensing applications. Our results demonstrate the benefits of the co-design paradigm in realizing Ndh2-quinone pairings with enhanced binding affinities, therefore highlighting the importance of considering protein-ligand engineering from a holistic co-design perspective.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"39"},"PeriodicalIF":3.0,"publicationDate":"2025-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144525898","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":"Design and evaluation of novel thiazolidinedione-oxadiazole derivatives as potent α-amylase inhibitors for antidiabetic therapy.","authors":"Pinky Arora, Aditi Rana, Azmat Ali Khan, Amer M Alanazi, Pankaj Wadhwa, Sonia Singla, Shubham Kumar, Rubal Kalra","doi":"10.1007/s10822-025-00619-y","DOIUrl":"https://doi.org/10.1007/s10822-025-00619-y","url":null,"abstract":"","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"38"},"PeriodicalIF":3.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504424","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":"Elucidating the binding mechanism of 1,4-bis[(3-Piperidino)propanamido]anthracen-9,10-dione (1,4-BPAQ) to human telomeric G-quadruplexes: a multi-technique approach including spectroscopic, calorimetric and molecular docking insights.","authors":"Priya Kumari, Kumud Pandav, Anuradha Panwar, Shrikant Kukreti, Mala Nath, Ritu Barthwal, Surat Kumar","doi":"10.1007/s10822-025-00615-2","DOIUrl":"https://doi.org/10.1007/s10822-025-00615-2","url":null,"abstract":"<p><p>Current research suggests that anthraquinone compounds have ability to interact with G4 DNA, leading to its stabilization and potential use as telomerase inhibitors in human cells. In light of this, a series of experiments to investigate the interaction between the compound 1,4-bis[(3-Piperidino)propanamido]anthracen-9,10-dione (1,4-BPAQ) and human telomeric DNA sequences in solutions rich in K⁺ and Na⁺ solutions was conducted. Employing various biophysical techniques and titration studies, it was observed that the binding of 1,4-BPAQ to G4 sequences resulted in notable changes in absorbance, including hypochromicity followed by hyperchromicity. Furthermore, extensive fluorescence quenching (94%) was accompanied by shifts in absorbance maxima, emission wavelength, and change in ellipticity (at 265 nm and 290 nm) was found in CD spectra. The data analysis indicated possible stoichiometries of 0.5:1 and 1:1 for the drug-quadruplex DNA complexes. Presence of a red shift suggested partial stacking between bases as primary interaction mode. Interestingly, binding affinity values were moderately higher in K⁺-rich solution. In addition, a significant thermal stabilization effect of up to 25 °C in K⁺ environment, while no such stabilization was observed in Na⁺ solution upon ligand binding. Molecular docking studies revealed similar binding energies across all conformational variations, despite distinct contact patterns between the ligand and three different G4 DNA conformations (2HY9/2JPZ/143D). This research demonstrated the potential anticancer activity of 1,4-BPAQ through MTT assay, with apoptosis activity observed at lower concentrations (IC₅₀ = 5.25 µM) against HepG2 cancer cells. These structural findings may hold significance in the context of drug development for anti-cancer therapies.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"37"},"PeriodicalIF":3.0,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144504425","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":"N-imidazopyridine derivatives of noscapine as potent tubulin-binding anticancer agents: chemical synthesis and cellular evaluation.","authors":"Pooja Dash, Pratyush Pragyandipta, Srinivas Kantevari, Pradeep Kumar Naik","doi":"10.1007/s10822-025-00617-0","DOIUrl":"https://doi.org/10.1007/s10822-025-00617-0","url":null,"abstract":"<p><p>In this study we present a novel class of N-imidazopyridine (impy) derivatives (12-15) of noscapine by tethering the imidazo[1,2-a]pyridine core to the N-atom of the isoquinoline ring of the lead molecule noscapine. These derivatives were found to have better docking scores (- 6.213 to - 7.897 kcal/mol) than noscapine (- 4.960 kcal/mol). Further, the calculated binding energy ranged between - 25.85 to - 35.57 kcal/mol, as determined by MD simulations and MM-PBSA calculations. Tubulin binding assay also revealed higher binding affinity for compounds 12, 13, 14, and 15 with the equilibrium dissociation constant (K_D) value of 78 ± 3.8 µM, 66 ± 1.7 µM, 56 ± 1.8 µM, and 35 ± 2.4 µM, respectively. These derivatives also exhibited potent cytotoxicity against breast cancer cell lines (MCF-7 & MDA-MB-231), with IC₅₀ values ranging from 3.7 to 32.4 µM, without any toxicity to normal human embryonic kidney (HEK) cells (IC₅₀ value > 1500 µM). FACS analysis revealed early apoptotic (45%) and late apoptotic cells (35%) when treated with the N-imidazopyridine derivatives (15) and arrested the cell cycle at the G2/M phase. Moreover, the impy derivative 15 was found to reduce the volume of implanted tumor in nude mice using xenografts of MCF-7 cells without any severe toxicity. Thus, we can infer that N-imidazopyridine-noscapinoids have increased potential as anticancer agents.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"36"},"PeriodicalIF":3.0,"publicationDate":"2025-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144482778","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":"Phenolic-based allosteric inhibition of PTP1B: unlocking new therapeutic potential for metabolic disorders.","authors":"Emadeldin M Kamel, Ahmed A Allam, Hassan A Rudayni, Fahad M Alshabrmi, Faris F Aba Alkhayl, Al Mokhtar Lamsabhi","doi":"10.1007/s10822-025-00616-1","DOIUrl":"10.1007/s10822-025-00616-1","url":null,"abstract":"<p><p>Protein tyrosine phosphatase 1B (PTP1B) plays a critical role in insulin signaling and is associated with various metabolic diseases, including type 2 diabetes. In this study, we investigated the inhibitory potential of five phenolic compounds isolated from Tamarix aphylla against PTP1B. Using molecular docking, molecular dynamics (MD) simulations, and ADMET analysis, we assessed the binding modes, stability, and pharmacokinetic properties of these compounds. The findings from in silico studies were validated by experimental in vitro enzyme activity assays, which showed that 3,3'-di-O-methylellagic acid and scutellarein exhibited the strongest inhibitory activities with IC₅₀ values of 3.77 ± 0.15 µM and 3.08 ± 0.36 µM, respectively. Both compounds were found to inhibit PTP1B via non-competitive inhibition, with K_i values of 3.90 µM and 3.40 µM. The free energy landscape (FEL) analysis confirmed stable binding conformations, while various MD parameter analyses indicated minimal structural perturbations in the enzyme, suggesting enhanced stability of the enzyme-ligand complexes. MM/PBSA calculations further supported the strong binding affinities of these compounds, highlighting their potential as PTP1B inhibitors. ADMET profiling indicated favorable pharmacokinetic properties, including good bioavailability and low toxicity risks. This study provides compelling evidence for the potential of phenolic compounds from Tamarix aphylla as therapeutic agents for PTP1B inhibition, offering new opportunities for the treatment of metabolic disorders.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"35"},"PeriodicalIF":3.0,"publicationDate":"2025-06-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473640","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":"An in-vitro and in-silico approaches in exploring the molecular contact of COVID-19 antiviral drug molnupiravir with human serum albumin: effect of binding on protein structure.","authors":"Mekala Prabhavathi, Bijaya Ketan Sahoo, Anna Tanuja Safala Bodapati, Bethala Samuel Raju","doi":"10.1007/s10822-025-00612-5","DOIUrl":"https://doi.org/10.1007/s10822-025-00612-5","url":null,"abstract":"<p><p>Protein structure and function are an important aspect in cellular organisms. The function of protein depends on its structural integrity. Changes in its structure may affect to its function leading to disease states. Therefore, understanding the structural integrity of protein both in its free and bound states are very important in medicinal chemistry and biophysical aspects of drug-protein interactions. The COVID-19 antiviral drug molnupiravir (MPV) was used for treatment of COVID-19 illness. The effect of MPV on secondary structure of human serum albumin (HSA) has been investigated from a biophysical perceptive using experimental and docking methods based on binding models. Binding strength of MPV with HSA was 10⁵ M^-1 order. Observed fluorescence quenching of HSA by MPV was static type with quenching constant of 10⁵ M^-1 order. Thermodynamic parameters (ΔG⁰, ∆H⁰, and ∆S⁰) suggested the spontaneity of contact with hydrogen bonding and van der Waals forces are being the primary forces. Binding-induced structural and conformational changes were visible from synchronous fluorescence and circular dichroism (CD) studies. The 3D fluorescence studies further complemented the conformational observations. Molecular docking of MPV with HSA showed its preferred location at site-1 and corroborated the experimental results. 2D diagram and ligplot assisted to analyse the interface residues in docked complex due to binding. The outcome of this study can be useful to decipher the binding behaviour of other drugs and in design of new drugs of better potential besides possible aid in pharmacodynamic studies of similar molecules.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"34"},"PeriodicalIF":3.0,"publicationDate":"2025-06-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144473639","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":"Computer-aided molecular and biological-immune modeling of illicium verum bioactive compounds employing the Egyptian Nile snail Biomphalaria alexandrina as a paradigm.","authors":"Alya Mashaal, Basma M Abou El-Nour, Fatma M Ismail, Eman A Elewa, Eman A Elnoby, Eman B Ebada, Ayaat G Mohammed, Manar F El-Sahmawy, Mariam M Mansour, Nermeen N Khames, Hend M Ghorab, Safaa A Osman, Alshimaa A Elsaid, Maryam M Abd-Alaziz, Asmaa S Zayed, Asmaa A Abo Elqasem","doi":"10.1007/s10822-025-00607-2","DOIUrl":"10.1007/s10822-025-00607-2","url":null,"abstract":"<p><p>In pursuit of sustainable biocontrol strategies, this study explores Illicium verum (star anise) as a dual-action anti-inflammatory/oxidative and molluscicidal agent using Biomphalaria alexandrina, the intermediate host of Schistosoma mansoni, as an eco-relevant in vivo model. Two experimental snail groups were employed: a control group and a treatment group exposed to a sublethal concentration of I. verum extract (LC₁₀ = 315 ppm). Through a combined pipeline of phytochemical profiling, computational simulations, and in vivo assays, we identified flavonoids and phenylpropanoids with potent bioactivity. Molecular docking and ADMET screening highlighted kaempferol, quercetin, and rutin as top ligands, which bind effectively to key snail proteins such as cytochrome c oxidase and actin. In vivo analyses confirmed immunomodulatory effects, and these findings were validated through oxidative/inflammatory biomarker assays, which revealed altered cytokine levels (IFN-γ, IL-2 and IL-6), tissue remodeling, and reduced oxidative stress. Histopathological and immunohistochemical evaluations revealed significant tissue alterations in the digestive gland and head-foot regions of treated snails. Gene and protein interaction networks supported these findings by linking compound action to immune and oxidative regulatory pathways. This integrative study demonstrated that Illicium verum contains bioactive compounds capable of modulating oxidative stress, immune responses, and tissue integrity in B. alexandrina as an animal model. Integrating phytochemical analysis with in silico and molecular simulations offers a powerful approach for understanding and optimizing bioactive compounds. While phytochemical profiling identifies key constituents such as flavonoids and phenylpropanoids, computational tools predict their binding to biological targets, pharmacokinetics, and safety. This combination not only streamlines the discovery of effective and low-toxicity compounds but also clarifies their mechanisms of action at the molecular level, enhancing both the precision and efficiency of experimental validation. These results position star anise as a promising, eco-friendly candidate for the development of novel molluscicidal and anti-inflammatory agents supporting sustainable disease control strategies.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"33"},"PeriodicalIF":3.0,"publicationDate":"2025-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12181124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144336186","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":"Thermodynamic free energy map for the non-oxidative glycolysis pathways.","authors":"Adittya Pal","doi":"10.1007/s10822-025-00604-5","DOIUrl":"10.1007/s10822-025-00604-5","url":null,"abstract":"<p><p>Designing reaction pathways that maximize the production of a target compound in a given metabolic network is a fundamental problem in systems biology. In this study, we systematically explore the non-oxidative glycolysis metabolic network, guided by the principle that reactions with negative Gibbs free energy differences are thermodynamically favored. We enumerate alternative pathways that implement the net non-oxidative glycolysis reaction, categorized by their length. Our analysis reveals several alternative thermodynamically favorable pathways beyond the experimentally reported ones. Additionally, we identify molecules within the network, such as 3-hydroxypropionic acid, that may have significant potential for further investigation.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"32"},"PeriodicalIF":3.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170709/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300909","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":"DTBA-net: Drug-Target Binding Affinity prediction using feature selection in hybrid CNN model.","authors":"Priya Mishra, Swati Vipsita","doi":"10.1007/s10822-025-00605-4","DOIUrl":"https://doi.org/10.1007/s10822-025-00605-4","url":null,"abstract":"<p><p>In drug discovery, virtual screening and repositioning rely on accurate Drug-Target Binding Affinity (DTBA) prediction to develop effective therapies. However, DTBA prediction remains challenging due to limited annotated datasets, high-dimensional biochemical data, and heterogeneous data sources, including chemical structures, biological sequences, and molecular interactions. These complexities hinder the development of unified deep-learning frameworks. To address these challenges, we propose DTBA-Net, a novel hybrid neural network model that enhances DTBA prediction accuracy and efficiency. DTBA-Net integrates optimal feature selection within a CNN architecture to predict DTBA. Protein sequences and compound structures are processed through a hybrid CNN that includes convolutional layers, a flattened layer, a Modified JAYA Algorithm for optimal feature selection, and dense blocks. The Modified JAYA algorithm selects relevant features, reduces computational overhead, and improves predictive performance. DTBA-Net was evaluated on two benchmark datasets, KIBA and DAVIS. On the DAVIS dataset, DTBA-Net attained an R-squared value of 0.95 and a Mean Absolute Error (MAE) of 0.17. Further validation using the drug Nirmatrelvir resulted in an R-squared value of 0.96, showcasing the model's robustness and scalability. Integrating a hybrid neural network with an optimized feature selection process accelerates model training and enhances prediction accuracy. DTBA-Net demonstrates promising potential for scalable, efficient, and accurate DTBA prediction, facilitating faster and more reliable drug discovery.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"31"},"PeriodicalIF":3.0,"publicationDate":"2025-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144300908","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":"Multitarget neuroprotective effects of β-sitosterol in diabetes-associated neurodegeneration: a coupled experimental/computational study.","authors":"Karishma Sen, Anita Sakarwal, Kamlesh Kumar, Heera Ram, Garima Singh, Vikas Kumar, Anil Panwar, Mukesh Kumar Yadav, Jing-Hua Wang","doi":"10.1007/s10822-025-00609-0","DOIUrl":"https://doi.org/10.1007/s10822-025-00609-0","url":null,"abstract":"<p><p>Diabetes often leads to neurodegenerative complications that complicate treatment. Exploring dietary components with neuroprotective properties could offer new therapeutic avenues. This study aimed to evaluate the neuroprotective potential of β-sitosterol against diabetes-associated neurodegenerative complications using a combined in silico and in vivo approach. β-Sitosterol exhibited significant neuroprotective effects in a diabetic neuropathy model. Compared to sitagliptin, β-sitosterol demonstrated stronger binding affinities to DPP4, acetylcholinesterase, and butyrylcholinesterase, along with more stable molecular dynamics profiles. In vivo, β-sitosterol treatment markedly improved glucose tolerance, insulin sensitivity, lipid profiles, and antioxidant capacity. Histological analysis revealed reduced neurodegenerative changes and enhanced neuronal integrity in the cortex and hippocampus. These findings suggest β-sitosterol as a promising therapeutic agent for managing diabetic neurodegeneration, warranting further research and potential clinical application.</p>","PeriodicalId":621,"journal":{"name":"Journal of Computer-Aided Molecular Design","volume":"39 1","pages":"30"},"PeriodicalIF":3.0,"publicationDate":"2025-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293077","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}