Discover molecules最新文献

{"title":"Computationally guided side chain optimization of nirmatrelvir for lead discovery against coronavirus main proteases.","authors":"Md Saidur Rahman, Shahidul M Islam","doi":"10.1007/s44345-026-00079-3","DOIUrl":"10.1007/s44345-026-00079-3","url":null,"abstract":"<p><p>To optimize Nirmatrelvir as an inhibitor of the MERS-CoV main protease (Mpro), we developed an automated RDKit-based iterative scaffold optimization framework that integrated fragment replacement, combinatorial library enumeration, and chemical feasibility filtering to generate 15,744 drug-like analogs through systematic substitutions at six positions on the Nirmatrelvir scaffold. Structural similarity to Nirmatrelvir was assessed using complementary 2D fingerprint and 3D shape-based analyses of the 15,953 designed analogs and a separate set of 13,090 molecular weight-matched ChEMBL compounds to examine the binding potency in both the modified and randomly selected compound cohorts. Based on the correlation between structural similarity and docking score of the modified molecules, a binding score (BS) approach was advanced to rapidly identify and rank promising lead compounds. Several top candidates exhibited improved binding characteristics compared to that of Nirmatrelvir. To assess the robustness of the BS approach, multiple computational methods were employed, including K_DEEP, molecular dynamics (MD) simulations, molecular mechanics/generalized Born surface area (MM/GBSA) free energy calculations, and Boltz-2. The BS ranking showed strong agreement with all computational validation methods, consistently identifying compounds with enhanced binding affinities and stable protein-ligand interactions. The top-ranked compounds, M1, M3, M5, and M6, identified by high Binding Score (BS) values (9.1-10.2), exhibited favorable MM/GBSA binding free energies ranging from - 31.7 to - 42.9 kcal/mol, K_DEEP-predicted binding affinities of - 9.5 to - 10.6 kcal/mol, and Boltz-2 predicted pIC₅₀ values of 10.0-11.8. Furthermore, for SARS-CoV-2 Mpro, BS scores also correlated well with available experimental half-maximal inhibitory concentration (IC₅₀) data and Boltz-2 predictions for Nirmatrelvir analogues. Collectively, these findings demonstrate that the BS approach may serve as an efficient strategy for screening, prioritizing, and accelerating the discovery of next-generation coronavirus Mpro inhibitors.</p><p><strong>Supplementary information: </strong>The online version contains supplementary material available at https://doi.org/10.1007/s44345-026-00079-3.</p>","PeriodicalId":521293,"journal":{"name":"Discover molecules","volume":"3 1","pages":"35"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13669040/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149218057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Food-derived antioxidant peptides undergo oxidative transformations that may alter their function and safety.","authors":"Matthew D Ezema, Harthika Mylvaganam, Apollinaire Tsopmo","doi":"10.1007/s44345-026-00063-x","DOIUrl":"10.1007/s44345-026-00063-x","url":null,"abstract":"<p><p>Bioactive peptides used in foods and nutraceuticals are frequently exposed to oxidizing environments that reshape their structure, function, and safety profile. Beyond acting as radical scavengers, peptides can undergo extensive modification by reactive oxygen species (ROS) and by oxidized lipid and sugar products that co-occur in complex food matrices. Mechanistic studies reveal that hydroxyl radicals, peroxyl radicals, and metal‑catalyzed H₂O₂ systems generate peptide hydroperoxides, carbonyls, backbone fragments, and covalent dimers in a sequence‑dependent manner, particularly at proline, tryptophan, tyrosine, and histidine residues. Parallel reactions with oxidized lipids, including lipid hydroperoxides and electrophilic aldehydes such as malondialdehyde and hydroxynonenal, drive additional layers of modification through trans‑oxidation, Schiff base formation, and Michael addition, yielding diverse adducts whose structures and stabilities differ markedly from classical ROS products. Glycation and glycoxidation further contribute carbonyl‑derived cross‑links and fluorophores in sugar‑rich systems. While the biological consequences of protein oxidation are well described, the functional and toxicological implications of oxidized bioactive peptides remain largely unexplored. Emerging evidence indicates that peptide hydroperoxides, lipid‑derived aldehyde adducts, and advanced glycoxidation/lipoxidation products can alter peptide bioavailability, immunoreactivity, redox behaviour, and cellular functions in cell and animal models. This review integrates current knowledge on the chemistry, analytical detection, and structural diversity of peptide oxidation products, highlights sequence‑specific reactivity patterns, and outlines safety considerations and research priorities for peptide‑based functional ingredients.</p>","PeriodicalId":521293,"journal":{"name":"Discover molecules","volume":"3 1","pages":"20"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13331881/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148393122","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Oscillatory dynamics in paclitaxel-proteinoid networks.","authors":"Panagiotis Mougkogiannis, Andrew Adamatzky","doi":"10.1007/s44345-026-00047-x","DOIUrl":"10.1007/s44345-026-00047-x","url":null,"abstract":"<p><p>Paclitaxel is a widely used microtubule-targeting chemotherapeutic, yet its intrinsic electrochemical behavior remains poorly understood. Here we investigate the electrochemical and oscillatory properties of paclitaxel incorporated into proteinoid microspheres that mimic cellular environments. Using scanning electron microscopy, cyclic voltammetry, electrochemical impedance spectroscopy, and square-wave voltammetry, we compare pure paclitaxel, proteinoid-paclitaxel mixtures, and related proteinoid systems. Incorporation of paclitaxel induces the formation of interconnected fibrous networks and enhances electrical conductivity by nearly two orders of magnitude relative to pure paclitaxel. The proteinoid-paclitaxel system exhibits diffusion-controlled redox behavior, long-term stable electrical oscillations, and high signal coherence. Spectral and nonlinear analyses reveal distinct dynamical regimes, including chaotic behavior in mixed proteinoid systems. These results establish proteinoid-paclitaxel assemblies as electrically active biomimetic platforms and suggest their potential as model systems for studying microtubule-related bioelectrical phenomena and bio-inspired signal processing.</p>","PeriodicalId":521293,"journal":{"name":"Discover molecules","volume":"3 1","pages":"6"},"PeriodicalIF":0.0,"publicationDate":"2026-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12961978/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147380518","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}