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  5. ADMETlab 3.0：全面升级的ADMET预测平台及其多领域应用

ADMETlab 3.0：全面升级的ADMET预测平台及其多领域应用

文献检索匿名用户发表于 2026年05月09日 15:3994阅读
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ADMETlab 3.0: an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support.

ADMETlab 3.0 is a comprehensive online platform that has been significantly updated to enhance its capabilities for predicting ADMET (Absorption, Distribution, Metabolism, Excretion, and Toxicity) parameters, along with physicochemical properties and medicinal chemistry characteristics crucial for drug discovery . This version is the second update to the web server, addressing limitations of its predecessors by offering broader coverage, improved performance, API functionality, and robust decision support .

Key Enhancements and Features of ADMETlab 3.0:

  • Expanded Data and Endpoints: ADMETlab 3.0 incorporates 119 features, representing an increase of 31 features compared to the previous version . The updated database is 1.5 times larger, containing over 400,000 entries, which contributes to its broader coverage and improved prediction accuracy .
  • Advanced Architecture and Performance: The platform utilizes a multi-task Deep Message Passing Neural Network (DMPNN) architecture, combined with molecular descriptors . This methodological advancement ensures rapid calculation speeds for each endpoint simultaneously, while also achieving superior performance in terms of accuracy and robustness .
  • API Functionality: To meet the increasing demand for programmatic access to large datasets, an Application Programming Interface (API) has been introduced in ADMETlab 3.0 . This allows users to integrate ADMETlab 3.0's prediction capabilities into their own computational workflows, facilitating high-throughput analysis and automation in drug discovery .
  • Uncertainty Estimates: A significant addition in this version is the inclusion of uncertainty estimates in the prediction results . This feature is invaluable for researchers, as it aids in the confident selection of candidate compounds for further studies and experiments by providing a measure of reliability for each prediction .
  • Public Accessibility: ADMETlab 3.0 is freely available for public access without the need for registration. It can be accessed at https://admetlab3.scbdd.com .
  • Authorship and Institutional Affiliations: The development of ADMETlab 3.0 involved researchers from multiple institutions, including the Xiangya School of Pharmaceutical Sciences, Central South University (Changsha, Hunan, P.R. China), the School of Chinese Medicine, Hong Kong Baptist University (Kowloon, Hong Kong SAR), and the School of Computer Science, National University of Defense Technology (Changsha, Hunan, P.R. China) . The corresponding authors include Li Fu, Shaohua Shi, Jiacai Yi, and Dongsheng Cao . The publication "Nucleic Acids Research," where ADMETlab 3.0 was described, has an impact factor of 13.1 .

Applications and Impact of ADMETlab 3.0 in Research:

ADMETlab 3.0 has been extensively utilized in various research studies to predict and evaluate the ADMET profiles of diverse compounds, contributing significantly to drug discovery, toxicology, and environmental health risk assessments.

  • Drug Discovery and Design:

    • Anti-inflammatory and Immunomodulatory Agents: Batatasin-III, a compound from Bletilla striata, was evaluated using ADMETlab 3.0, which predicted favorable drug-likeness, bioavailability, and low toxicity, supporting its potential as a therapeutic agent for ulcerative colitis through multitarget modulation of inflammation, kinase regulation, and epithelial repair .
    • Anticancer Drug Development: Novel analogues of nilutamide (NLM) were designed as potential antiandrogen agents for prostate cancer therapy . ADMETlab 3.0 was used to calculate ADMET scores for these analogues, with NLM34 and NLM40 showing optimized pharmacokinetic profiles and reduced toxicity compared to the parent compound, making them promising candidates . Similarly, new 4-benzenesulfonamide derivatives of pyrazolo[1,5-a][1,3,5]triazine were synthesized and evaluated for anticancer activity, with ADMETlab 3.0 predicting favorable ADMET profiles for compounds 4, 5, and 7, which exhibited potent activity against various cancer cell lines and low toxicity .
    • Antiplasmodial Compounds: n-Hexadecanoic acid (HA) was investigated for its multi-stage antiplasmodial potency and toxicity . ADMETlab 3.0 was employed to predict its absorption, distribution, metabolism, excretion, and toxicity profiles, which, along with in vivo studies, indicated that HA is safer at lower doses and is a potential drug candidate for malaria .
    • Erectile Dysfunction Treatment: The ADMET properties of molecules like L-arginine, L-citrulline, resveratrol, alpha-lipoic acid, and rutin, potentially involved in erectile dysfunction (ED) treatment, were determined using ADMETlab 3.0 . The analysis showed L-arginine and L-citrulline to have low toxicity and positive therapeutic effects, while resveratrol showed promising data but required further investigation into its potential toxicity and metabolic interactions .
    • Major Depressive Disorder Treatment: A duloxetine (DLX) analog, DLX48, was designed and evaluated in silico as a potential next-generation treatment for Major Depressive Disorder (MDD) . ADMETlab 3.0 predictions indicated that DLX48 complies with drug-likeness rules, exhibits improved aqueous solubility and optimal lipophilicity, and crucially, shows no predicted hepatotoxicity or genotoxicity, suggesting enhanced pharmacological efficacy and a reduced toxicity profile .

  • Toxicology and Safety Assessment:

    • Environmental Pollutants:
      • 6PPDQ-Induced Hepatotoxicity: ADMETlab 3.0 was utilized to predict the physicochemical properties and multiorgan toxicity of 6PPDQ, a rubber tire-derived environmental pollutant . The platform's predictions contributed to a comprehensive mechanistic framework for 6PPDQ-induced liver injury, highlighting mechanisms such as apoptosis, inflammation, and lipid metabolic disturbances .
      • Microplastics (MPs) and Allergic Rhinitis: The toxicity profiles of typical microplastics (polyethylene, polypropylene, polyvinyl chloride, polystyrene) were evaluated using ADMETlab 3.0 . The analysis revealed that MPs exhibit significant respiratory and ocular toxicity, influencing allergic rhinitis pathogenesis through pathways involving apoptosis, mitochondrial autophagy, and inflammation .
      • DINCH-Induced Hepatotoxicity: ADMETlab 3.0 was used to predict the hepatotoxicity and carcinogenicity of Diisononyl cyclohexane-1,2-dicarboxylate (DINCH), a phthalate substitute . The predictions helped elucidate the primary mechanisms by which DINCH may induce hepatotoxicity, primarily by upregulating TNF, TP53, and PPARG .
      • 6PPD and 6PPD-quinone Respiratory Toxicity: ADMETlab 3.0, along with ProTox-II, was used to predict the respiratory hazard potential of 6PPD and its ozone-derivative, 6PPD-quinone . The study found that these emerging pollutants disrupt mitochondrial energy metabolism, dysregulate apoptotic pathways, and activate inflammatory cascades, leading to respiratory inflammation .
      • Organophosphorus Pesticides (OPs): ADMETlab 3.0 was applied to predict toxicity indicators for parent OPs and their environmental transformation products . The findings indicated that unrestricted OPs like phorate, parathion, and chlorpyrifos have a high probability of toxicity, and their transformation products pose similar comprehensive toxicity risks, leading to the creation of a "special attention list" for OPs .
    • Drug-Induced Toxicity:
      • Vorasidenib Safety Profile: An in silico analysis of Vorasidenib, an IDH1/2 inhibitor approved for grade 2 astrocytomas and oligodendrogliomas, was conducted using ADMETlab 3.0 and other computational tools . The results suggested potential risks of drug-induced liver injury (DILI), hepatotoxicity, neurotoxicity, nephrotoxicity, cardiotoxicity (including hERG channel blockade), genotoxicity, and carcinogenicity, underscoring the need for careful patient monitoring .
    • Arecoline-Induced Oral Cancer: Toxicity profiling of arecoline, a carcinogen from betel nut, was performed using ProTox-3.0 and ADMETlab databases . The study investigated the molecular mechanisms of arecoline-induced oral cancer, identifying core targets like TP53, TNF, IL6, and CASP3, which interfere with cellular growth, inflammatory responses, and apoptotic mechanisms .

Comparison with ADMETlab 2.0:

While ADMETlab 3.0 represents a significant upgrade, ADMETlab 2.0 has also been used in various studies for ADMET predictions.

  • Pharmacokinetic and Bioactivity Prediction: ADMETlab 2.0 was utilized to predict the pharmacokinetic properties and bioactivity profiles of the main constituents of Foeniculum vulgare essential oil (FVEO) . This was part of a study investigating FVEO's effects on scopolamine-induced cognitive deficits in zebrafish, where FVEO was found to improve cognitive performance and reduce oxidative stress .
  • Comparison of Thiosemicarbazide and Semicarbazide Derivatives: ADMETlab 2.0 software was used for in silico analysis to compare the ADMET profiles of thiosemicarbazide and semicarbazide derivatives with proven antitumor activity . The comparative analysis revealed that semicarbazides generally have more favorable intestinal absorption, lower biological activity but higher selectivity, and lower risk of drug interactions . Thiosemicarbazides, on the other hand, showed a higher probability of metabolic activity with increased toxicity, higher plasma protein binding, a lower unbound fraction, and a longer half-life . The study concluded that semicarbazides are better candidates for anticancer drug trials due to their more favorable pharmacokinetic and pharmacodynamic profiles and lower toxicity .

In summary, ADMETlab 3.0 is a robust and highly capable platform that significantly advances in silico ADMET prediction. Its expanded coverage, improved performance, API integration, and uncertainty estimates make it an indispensable tool for accelerating drug discovery and enhancing toxicology assessments across a wide range of applications.

References

1ADMETlab 3.0: an updated comprehensive online ADMET prediction platform enhanced with broader coverage, improved performance, API functionality and decision support.PubMed

Li Fu, Shaohua Shi, Jiacai Yi, et al.
ADMETlab 3.0 is the second updated version of the web server that provides a comprehensive and efficient platform for evaluating ADMET-related parameters as well as physicochemical properties and medicinal chemistry characteristics involved in the drug discovery process. This new release addresses the limitations of the previous version and offers broader coverage, improved performance, API functionality, and decision support. For supporting data and endpoints, this version includes 119 features, an increase of 31 compared to the previous version. The updated number of entries is 1.5 times larger than the previous version with over 400 000 entries. ADMETlab 3.0 incorporates a multi-task DMPNN architecture coupled with molecular descriptors, a method that not only guaranteed calculation speed for each endpoint simultaneously, but also achieved a superior performance in terms of accuracy and robustness. In addition, an API has been introduced to meet the growing demand for programmatic access to large amounts of data in ADMETlab 3.0. Moreover, this version includes uncertainty estimates in the prediction results, aiding in the confident selection of candidate compounds for further studies and experiments. ADMETlab 3.0 is publicly for access without the need for registration at: https://admetlab3.scbdd.com.

2Mill. Mitigates Scopolamine-Induced Cognitive Deficits via Antioxidant and Neuroprotective Mechanisms in Zebrafish.PubMed

Ion Brinza, Razvan Stefan Boiangiu, Elena Todirascu-Ciornea, et al.
Mill. (Apiaceae) is an aromatic medicinal plant known for its anti-inflammatory, antispasmodic, antiseptic, carminative, diuretic, and analgesic properties. This study aimed to investigate the effects of essential oil (FVEO; 25, 150, and 300 μL/L) on the cognitive performance and brain oxidative stress in a scopolamine (SCOP; 100 μM)-induced zebrafish model of cognitive impairment. Additionally, the pharmacokinetic properties and bioactivity profiles of the main FVEO constituents were predicted to be used in silico tools, including SwissADME, pkCSM, PASS online, and ADMETlab 2.0. Behavioral assays, novel tank diving test (NTT), Y-maze, and novel object recognition (NOR) test, were used to evaluate anxiety-like behavior, spatial memory, and recognition memory, respectively. Biochemical assessments of acetylcholinesterase (AChE) activity and oxidative stress biomarkers were also conducted. The results demonstrated that FVEO significantly improved cognitive performance in SCOP-treated zebrafish, normalized AChE activity, and reduced oxidative stress in the brain. These findings suggest the therapeutic potential of FVEO in ameliorating memory impairment and oxidative damage associated with neurodegenerative disorders such as Alzheimer's disease (AD).

3Network pharmacology and molecular dynamics simulation elucidate the potential mechanism of Batatasin-III in Bletilla striata against ulcerative colitis.PubMed

Yao Tong, Ruichao Chen, Huqing Ling, et al.
Batatasin-III, a phenanthrene compound isolated from Bletilla striata, has demonstrated potential anti-inflammatory and immunomodulatory effects, yet its precise molecular mechanism against ulcerative colitis (UC) remains largely unexplored. This study integrates network pharmacology, molecular docking, ADMET profiling, and molecular dynamics (MD) simulations to systematically elucidate the multitarget therapeutic potential of Batatasin-III in UC treatment. Batatasin-III-related targets were retrieved from SwissTargetPrediction, while UC-associated genes were collected from GeneCards and OMIM databases. A total of 101 intersecting genes were identified and subjected to PPI network construction using STRING and topological analysis in Cytoscape. GO and KEGG enrichment analyses revealed significant involvement in key biological processes and pathways such as MAPK signaling, PI3K-Akt signaling, protein phosphorylation, and cytokine-mediated inflammation. Molecular docking showed strong binding affinities between Batatasin-III and core targets ALB (- 8.4 kcal/mol), MAPK3 (- 8.2 kcal/mol), ESR1 (- 7.7 kcal/mol), and HSP90AA1 (- 5.7 kcal/mol). ADMET evaluation via ADMETlab 3.0 predicted favorable drug-likeness, bioavailability, and low toxicity for Batatasin-III. Subsequent 100-ns MD simulations demonstrated high conformational stability (RMSD < 3.7 Å), sustained hydrogen bonding, and compact binding dynamics, particularly in ESR1-Batatasin-III and MAPK3-Batatasin-III complexes. MM/PBSA binding free energy analysis supported strong binding thermodynamics, with ALB-Batatasin-III exhibiting the most favorable ΔG_bind (- 29.65 kcal/mol). Residue energy decomposition highlighted critical contributions from TYR411, MET125, HIS524, and ASN171, among others. To validate these computational predictions, in vitro assays were conducted. A CCK-8 assay confirmed Batatasin-III was non-cytotoxic to RAW 264.7 macrophages. In an LPS-stimulated model, Batatasin-III significantly and dose-dependently inhibited the mRNA expression of key pro-inflammatory mediators, including TNF-α, IL-6, IL-1β, and NOS2. Overall, Batatasin-III may exert therapeutic effects against UC through multitarget modulation of inflammation, kinase regulation, and epithelial repair, primarily via the MAPK and PI3K-Akt pathways. This study provides a validated mechanistic foundation for Batatasin-III as a potential bioactive compound for UC intervention and supports further in vivo validation.

4Combined Analysis of Network Toxicology and Multiomics Revealed the Potential Mechanism of 6PPDQ-Induced Hepatotoxicity in Mice.PubMed

Bo Li, Chenchen Xu, Duo Zhang, et al.
6PPDQ, a rubber tire-derived environmental pollutant, exhibits significant hepatotoxicity. However, its hepatotoxic mechanisms remain insufficiently studied and systematically evaluated. This study integrated network toxicology, transcriptomics, and metabolomics to investigate its toxicity mechanisms. ADMETlab 3.0 was used to predict physicochemical properties and multiorgan toxicity. The targets related to 6PPDQ and liver injury were obtained from public databases, and a protein-protein interaction (PPI) network was constructed to identify key targets. Meanwhile, molecular docking was performed to assess 6PPDQ's binding affinity to core proteins. Transcriptomics and differential gene expression analysis were performed on the livers of Kunming mice exposed to 4 mg/kg 6PPDQ to explore transcriptomic alterations, while metabolomic profiling identified disrupted metabolic pathways. Network toxicology results reveal that 6PPDQ primarily induces hepatotoxicity through apoptosis, inflammation, and lipid metabolic disturbances. Key targets, including , , , , , , and , are identified, with strong binding affinities suggesting direct interactions. Transcriptomic and metabolomic analyses further confirms disruptions in TNF, NF-kappa B, oxidative phosphorylation, autophagy pathways, and glycerolipid metabolism. Overall, this study provides a comprehensive mechanistic framework for 6PPDQ-induced liver injury in mice and provides a new perspective for subsequent studies on the mechanism of 6PPDQ hepatotoxicity.

5Comparison of ADMET profile between thiosemicarbazide and semicarbazide derivatives regarding anticancer properties.PubMed

Łucja Justyna Walczak, Mariola Herbet
INTRODUCTION: The incidence of cancer is constantly increasing, and current cytostatics are not effective enough and cause serious side effects. Thio/semicarbazide derivatives seem to be promising candidates for anticancer drugs. This systematic review aimed to analyze comparatively the ADMET profiles of thiosemicarbazides and semicarbazides with proven antitumor activity published through August 2024. METHODS: A search of PubMed, ScienceDirect and Google Scholar databases was performed. Qualified compounds were subjected to in silico analysis using ADMETlab 2.0 software. The data were statistically analyzed (Student's t-test, Mann-Whitney U test, Chi). RESULTS: Comparative analysis showed that semicarbazides have more favorable intestinal absorption properties and lower biological activity but have higher selectivity of action and lower risk of drug interactions. Thiosemicarbazides have a higher probability of metabolic activity with concomitant increased toxicity. These compounds show significantly higher levels of binding to plasma proteins, a lower average percentage of the unbound fraction, and a longer half-life. CONCLUSIONS: In light of anticancer therapies, thiosemicarbazides can cause increased oxidative stress and DNA damage, which is one strategy for cancer treatment. However, semicarbazides are better candidates for anticancer drug trials because of their better pharmacokinetic and pharmacodynamic profiles and lower toxicity.

6Comparison of PDE-5 inhibitors used in erectile dysfunction with some candidate molecules: A study involving molecular docking, ADMET, DFT, biological target, and activity.PubMed

Süleyman Sağır, Velid Unsal, Erkan Oner, et al.
Erectile dysfunction (ED) is a urological condition defined as the inability of a man to achieve or maintain an erection. This condition negatively affects his sexual performance and the performance of his partner. Phosphodiesterase type 5 (PDE5) inhibitors are commonly used to treat ED. Arginase II plays an important role in regulating L-arginine to NO synthase in the smooth muscle of the human corpus cavernosum of the penis. NO is a molecule essential for regulating a variety of functions, including arterial blood pressure, penile erection, and energy balance. Substances such as vardenafil, alprostadil, papaverine, and resveratrol increase NO production, thereby supporting sexual function and vascular health. Additionally, NO donors such as L-arginine, L-citrulline, and α-lipoic acid provide effective alternatives when used in combination with PDE5 inhibitors. Medications used in the treatment of ED include vardenafil, alprostadil, and papaverine. In addition, although molecules such as L-arginine, citrulline, resveratrol, alpha-lipoic acid, and rutin are thought to play a role in ED, their pharmacological and molecular effects have not been sufficiently elucidated. The aim of this study was to investigate the effects of these molecules in the treatment of ED by computer-based calculations, to obtain new information about them and to inspire new treatment strategies for ED. The physicochemical, molecular and pharmacokinetic properties of the compounds were determined by SwissADME software, and ADMET (absorption, distribution, metabolism, excretion and toxicity) data were determined by ADMETlab 3.0 software. Biological target and activity data were obtained by MolPredictX and PASS Online software. While the Gaussian 09 program was used for DFT calculations, PyMOL, AutodockTools 4.2.6, AutoDock Vina, and Biovia Discovery programs were used for molecular docking studies. It was found that L-arginine, citrulline, resveratrol and α-lipoic acid were well absorbed from the intestine, while rutin showed limited absorption. When their metabolic risks were evaluated, L-arginine and citrulline were found to have lower toxicity. Molecular docking results of rutin and resveratrol were remarkable. The electronic properties of the compounds were explained by DFT calculations. L-arginine and citrulline were found to have low toxicity and positive therapeutic effects. L-arginine and citrulline stand out as promising candidates for future research. Although resveratrol data are promising, unfortunately their potential toxicity and metabolic interactions require further investigation. It is important to learn more about these compounds or conduct research to improve their therapeutic efficacy. Although computer-based calculations play an important role in toxicity predictions, drug interactions, pharmacokinetics and toxicity properties should be carefully evaluated.

7Microplastic exposure and allergic rhinitis: Network toxicology, and molecular docking insights.PubMed

Yaojun Wang, Dandan Xu
BACKGROUND: Microplastics (MPs), ubiquitous environmental pollutants, are increasingly associated with global health risks, yet their role in allergic rhinitis (AR) pathogenesis remains poorly understood. METHODS: Toxicity profiles of four typical MPs (polyethylene [PE], polypropylene [PP], polyvinyl chloride [PVC], polystyrene [PS]) were evaluated using ADMETlab 3.0. MP-related targets and AR-associated genes were integrated from the CTD database and GSE43523 dataset. Functional enrichment (GO/KEGG) and PPI network analysis (STRING/GeneMANIA) were performed on overlapping genes. LASSO regression and expression validation identified key targets, and molecular docking (Autodock Vina) assessed interactions with potential therapeutics predicted by CTD. RESULTS: ADMET analysis revealed MPs exhibit significant respiratory toxicity and ocular toxicity. We identified 301 MP toxicity targets, 1,026 AR differentially expressed genes (DEGs), and 15 overlapping pathogenic targets. Functional enrichment (GO/KEGG) demonstrated MPs disrupt respiratory mucosal homeostasis via apoptosis, mitochondrial autophagy, and inflammatory pathways. PPI network analysis and LASSO regression pinpointed DNAJB9, SQSTM1, and MAPK9 as core mediators: these genes were significantly downregulated in AR patients (P < 0.05) and displayed robust diagnostic performance (AUC = 0.82-0.93). Molecular docking revealed resveratrol binds these targets with high affinity, surpassing SQSTM1 (-5.8 kcal/mol) and MAPK9 (-6.8 kcal/mol), suggesting its potential to block MP-induced dysregulation. CONCLUSIONS: MPs drive AR pathogenesis through respiratory toxicity pathways, with DNAJB9, SQSTM1, and MAPK9 serving as critical molecular mediators. Resveratrol, by modulating target-mediated programmed cell death, emerges as a promising therapeutic candidate for mitigating MP-induced AR.

8and evaluations of multistage antiplasmodial potency and toxicity profiling of n-Hexadecanoic acid derived from .PubMed

F I D Afolayan, R A Odeyemi, R A Salaam
BACKGROUND: Despite the widely reported potentials of n-Hexadecanoic acid (HA) as a bioactive, its multi-stage antiplasmodial activity and toxicity profiles remain largely unknown. METHODOLOGY: Thus, this study uses a combination of approaches and studies to assess the inhibitory activities of HA at different stages of the Plasmodium lifecycle, antiplasmodial performance, and toxicity profiles. The HA was retrieved from the PubChem database, while antiplasmodial target proteins from different stages of the life cycle were collated from the Protein Databank (PDB). Molecular Docking and Visualization were conducted between the compound and target proteins using AutoVina PyRx software and Biovia Discovery Studio, respectively. Also, the AdmetLab 3.0 algorithm was used to predict the absorption, Distribution, Metabolism, Excretion, and Toxicity (ADMET) profiles of HA. Based on a 4-day suppressive test, the antiplasmodial activity against the strain in mice was evaluated. Furthermore, subacute toxicity and micronucleus assays were used for further toxicity assessment. RESULTS: The molecular docking analysis indicates multi-stage, multi-target potentials of HA with favourable ligand-receptor complexes across the four stages. Meanwhile, the mice administered with 100 mg/kg, 50 mg/kg, and 10 mg/kg of HA demonstrated considerable chemosuppression in a dose-dependent manner of 89.74%, 83.80%, and 71.58% percentage chemosuppression, respectively, at < 0.05. The ADMET prediction, histopathological tests, and micronucleus assays show that HA is safer at a lower dose. CONCLUSION: This study showed that n-Hexadecanoic acid is a potential drug candidate for malaria. Hence, it is recommended for further molecular and biochemical investigations.

9Unraveling DINCH - Induced hepatotoxicity mechanisms via network toxicology and molecular docking with experimental validation.PubMed

Jingxin Xin, Changxu Zhou, Ying Wang, et al.
Phthalates, as a class of known endocrine disruptors, have been controversial because of their potential carcinogenicity and toxicity. Diisononyl cyclohexane-1,2-dicarboxylate (DINCH) is considered to be less toxic and more prone to environmental degradation, and is widely used as a substitute for phthalate. With the increasing use of DINCH in consumer products and industrial materials, the frequency of its detection in the air and human urine has also increased, which has aroused concern about its potential toxicity in food safety. Despite the increasing popularity of DINCH, toxicological studies on this topic are still limited. This study first predicted the hepatotoxicity and carcinogenicity of DINCH via the ADMETlab 3.0 platform. Next, the potential hepatotoxic genes associated with DINCH were collected through multiple databases, and a gene network was constructed. Through proteinprotein interaction, GO enrichment and KEGG pathway analyses, we elucidated the primary mechanism by which DINCH may induce hepatotoxicity. The expression of the selected key genes in related diseases was subsequently validated via the liver cancer database of TCGA and the NASH dataset of GEO. In addition, molecular docking technology and dynamics simulation were used to simulate the interaction and binding ability between DINCH and the core target. Cell experiments verified that DINCH increases hepatotoxicity primarily by upregulating TNF, TP53, and PPARG. In summary, this study elucidates the potential biological mechanisms of DINCH-induced hepatotoxicity, providing new scientific insights for the prevention and management of related toxicities.

10Assessing novel analogues of nilutamide as a human androgen receptor antagonist: A detailed investigation of drug design using a bioisosteric methodology including ADMET profiling, molecular docking studies and molecular dynamics simulation.PubMed

Ajay Kumar Gupta, Yogita Sahu, Dipti Pal, et al.
Cancer is a significant health and economic concern worldwide. Prostate cancer (PC) ranks as the fourth leading cause of global death and is the second most prevalent malignancy in males. Androgens are essential for the progress and growth of the prostate gland. PC is caused by androgens binding to receptors, which activates genes that promotes the development of PC. Nilutamide (NLM) is an antiandrogen medicine used in the treatment of PC. However, throughout treatment, it induces various toxicities and leads to resistance in patients. The objective of the work was to designed and evaluated safer NLM analogues using computational approaches with optimized pharmacokinetic profiles and less toxicity. Newer bioisosteres of the designed NLM analogues and their ADMET scores were calculated using the MolOpt and ADMETlab 3.0 tools, respectively. We conducted docking investigations of the designed ligands using AutoDock Vina software. The MolOpt web server produces 1575 bioisosteres of NLM using the scaffold transformation method. The 47 bioisosteres were selected based on pharmacokinetic profiles, drug likeness (DL) and drug score (DS) prediction scores and were determined to be optimum to excellent in comparison to NLM. The analogues NLM28, NLM31, NLM34, NLM38, NLM40, NLM44, NLM45, and NLM47 exhibited favorable interactions and docking scores with the protein (PDB ID: 2AM9). The molecular dynamics (MD) simulation results revealed that the NLM34 and NLM40 complexes were found stable during the 100 ns run. The findings indicate that the NLM analogues, particularly NLM34 and NLM40 have the potential to be used as promising antiandrogen agents for PC therapy.

11Respiratory toxicity mechanism of 6PPD and 6PPD-quinone: An integrated study based on network toxicology and molecular docking.PubMed

Gang Li, Dan Li, Weibin Zhai, et al.
The widespread distribution of environmental contaminants poses a significant threat to public health. N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its ozone-derivative, 6PPD-quinone (6PPD-Q), are emerging pollutants that propagate through particulate matter and aerosols, exerting detrimental effects on the respiratory system. However, their specific pathogenic mechanisms remain unclear. This study employs integrated network toxicology and molecular docking to elucidate the molecular basis of 6PPD/6PPD-Q-induced respiratory toxicity. Respiratory hazard potential was predicted using ADMETlab 3.0 and ProTox-II. Potential targets were identified through multi-database mining (BindingDB, ChEMBL, SwissTargetPrediction, TargetNet), with disease-associated targets categorized into acute and chronic respiratory damage using GeneCards and OMIM. Intersectional analysis via Venn diagrams, STRING, and Cytoscape revealed compound-specific targets (EGFR for 6PPD; FYN for 6PPD-Q) and five shared targets (NR3C1, MAPK14, RELA, CYCS, JAK2). Enrichment analysis using DAVID indicated significant associations with mitochondrial energy metabolism, oxidative stress, apoptosis and neuroactive ligand-receptor interactions (p < 0.05). Molecular docking and molecular dynamics simulations confirmed that both compounds showed high affinity binding to key toxicity targets (binding energy <-20.92 kJ/mol), and revealed the interaction mode of these two compounds with the key target CYCS. Mechanistically, 6PPD and 6PPD-Q disrupt the mitochondrial electron transport chain, dysregulate apoptotic pathways, and activate NF-κB/JAK-STAT inflammatory cascades, leading to respiratory inflammation. This study establishes a comparative toxicological framework for 6PPD and 6PPD-Q, identifying actionable molecular targets and mechanistic pathways for respiratory toxicity, and highlights the utility of computational toxicology strategies in environmental health risk assessment.

12New 4-Benzenesulfonamide Derivatives of Pyrazolo[1,5-] [1, 3, 5]triazine as Purine Bioisosteres: Development, Synthesis, and Anticancer Perspective.PubMed

Ivan Semenyuta, Stepan Pilyo, Bohdan Demydchuk, et al.
INTRODUCTION: Seven new 4-[2-(dichloromethyl)pyrazolo[1,5-a][1,3,5]triazine derivatives were investigated for anticancer activity, possible molecular mechanisms of anticancer action, and ADMET properties. METHODS: The 4-benzenesulfonamide derivatives of pyrazolo[1,5-a][1,3,5]triazine were synthesized using the condensation of N-(2,2-dichloro-1-cyanovinyl)-amides IV with 1H-pyrazol-5-amine. Compound antitumor activities were evaluated using the NCI-60 human cancer cell line. AutoDockTools and AutoDock Vina software were used for molecular modeling. Using the ADMETlab 3.0 and pkCSM web sources, the ADMET properties of compounds 4, 5, and 7 were calculated. RESULTS: Seven new pyrazolo[1,5-a][1,3,5]triazine derivatives were synthesized. The compounds 4, 5, and 7 exhibit high activity >1 μM against leukemia, colon, and renal cancer. Compound 4 exhibited the most potent activity, with IC values of 0.32 μM against leukemia, 0.49-0.89 μM against colon cancer, and 0.92 μM against renal cancer. Molecular modeling has demonstrated a potential antitumor mechanism involving CDK. The predicted ADMET profile of compounds 4, 5, and 7 is favorable. DISCUSSION: The seven novel pyrazolo[1,5-a][1,3,5]triazines, as purine bioisosteres, were developed, synthesized, and investigated by in vitro and in silico methods. CONCLUSION: Seven novel pyrazolo[1,5-a][1,3,5]triazine derivatives exhibited anticancer activity against the NCI-60 cancer cell lines. The compounds 4, 5, and 7 demonstrated strong anticancer activity, with growth inhibition (GI) values exceeding 50% across all nine cancer types tested. The most active compound, 4, is against leukemia, colon cancer, renal cancer, and lung cancer. All compounds exhibit low toxicity, with LC50 values of 100 μM or greater. The molecular docking of compounds 4, 5, and 7 revealed the potential to inhibit cancer-associated cyclin-dependent kinases. The predicted ADMET profiles of their compounds are favorable, providing a basis for further improvement of their anticancer activity.

13Toxicological insights and safety considerations of vorasidenib in grade 2 astrocytoma and oligodendroglioma.PubMed

Gabriel Vinícius Rolim Silva, M Aktaruzzaman, Umberto Laino Fulco, et al.
Vorasidenib, a dual inhibitor of isocitrate dehydrogenase 1 and 2 (IDH1/2), has shown promise as a therapeutic agent following its recent FDA approval for the treatment of grade 2 astrocytomas and oligodendrogliomas harboring IDH mutations in patients 12 years of age and older following surgery. While Vorasidenib offers significant potential in targeting altered metabolic pathways in low-grade gliomas, its comprehensive toxicologic and safety profile has not been adequately explored. This research letter addresses this critical gap by presenting an in silico analysis of the potential toxicologic effects of Vorasidenib. Using computational tools - ADMETlab 3.0, FAF-Drugs 4.1, DeepPK, vNN-ADMET, Pred-hERG 5.0, ADVERPred, PreADMET, and ADMET-AI - and databases such as ChEMBL, PubChem, and ChemSpider, we evaluated the key physicochemical properties and predicted ADMET profiles of Vorasidenib, along with a comparative analysis of two other drugs, namely Ivosidenib and Enasidenib. Our results suggest potential risks associated with drug-induced liver injury (DILI) and hepatotoxicity, with structural properties indicative of hepatocellular damage during and after treatment. The low clearance rates associated with the low maximum recommended dose suggest that Vorasidenib may accumulate in the bloodstream over time, increasing the likelihood of toxic reactions. In addition, the predictive models indicate concerns for neurotoxicity, nephrotoxicity and cardiotoxicity, including potential blockade of hERG channels leading to QT interval prolongation and cardiac arrhythmias. Importantly, the analysis also indicates risks of genotoxicity and carcinogenicity, raising concerns about promoting additional tumor formation in patients already prone to malignancies. These results emphasize the need for further preclinical and clinical studies to validate the safety of Vorasidenib. A comprehensive understanding of the toxicologic profile is critical to ensure that the therapeutic benefit for patients with IDH1/2-mutated low-grade gliomas is not compromised by potential adverse effects. Careful monitoring of patients and tailored therapeutic strategies are essential to optimize clinical outcomes and guide physicians in the safe use of Vorasidenib in clinical practice.

14Organophosphorus Pesticides Management Strategies: Prohibition and Restriction Multi-Category Multi-Class Models, Environmental Transformation Risks, and Special Attention List.PubMed

Yingwei Wang, Lu Wang, Yufei Li
Organophosphorus pesticides (OPs) have become one of the most widely used pesticides in Chinese agriculture; however, methods to identify potential restrictions on OPs molecules are lacking. Therefore, this study retrieved the OPs restriction list and constructed eight multi-class, multi-category machine learning models for OPs restrictions. Among these, the random forest (RF) model demonstrated excellent predictive performance, as it was successfully validated and applied. Potential environmental transformation products of OPs were obtained using EAWAG-BBD software, while toxicity indicators for the parent OPs and their transformation products were predicted with ADMETlab 3.0 software. This study found that unrestricted OPs, such as phorate, parathion, and chlorpyrifos, exhibited a high probability of toxicity. Additionally, the environmental transformation products of OPs posed similar comprehensive toxicity risks as the parent compounds. A special attention list for OPs was created based on the toxicity risks of unrestricted parent OPs and their transformation products, using standard deviation classification. Phorate and parathion were identified as OPs requiring special attention. This paper aims to provide an effective method for identifying the potential restriction levels of OPs and to propose an evaluation system that comprehensively considers the health risk, thereby supporting the improvement and optimization of management and usage strategies for OPs.

15Molecular mechanisms of arecoline-induced oral cancer: a network toxicology and molecular docking techniques integrated analysis.PubMed

Linghan Leng, Xin Wang, Hao Wang, et al.
The IARC classified betel nut as Group 1 carcinogen (2004) and arecoline as Group 2B carcinogen (2020), with approximately one-third of global oral cancer cases attributed to smokeless tobacco or betel nut consumption. While current evidence establishes an association between arecoline and oral cancer, the underlying molecular mechanisms remain complex and poorly elucidated. This study employs network toxicology integrated with molecular docking techniques to systematically investigate the potential molecular pathogenesis of arecoline-induced oral cancer, aiming to provide novel insights for targeted therapeutic strategies. The SMILES structure of arecoline was retrieved from PubChem for foundational data preparation. Toxicity profiling was conducted using ProTox-3.0 and ADMETlab databases. Potential targets of arecoline were identified via STITCH and SwissTargetPrediction. Oral cancer-related targets were collated from GeneCards, OMIM, and TTD. Intersection analysis between arecoline targets and oral cancer-associated targets was performed to identify shared targets, which were further utilized to construct compound-target regulatory network and subjected to PPI, GO, and KEGG analyses. Core targets driving oral cancer were screened using the cytoHubba plugin. Then, the correlation between core targets and immune cell infiltration in oral cancer was explored, and molecular docking validated the binding affinity of arecoline to core targets. Finally, Gromacs 2022.3 software was used to simulate the molecular dynamics of the complexes obtained by molecular docking for 100 ns. Using the STITCH and SwissTargetPrediction databases, a total of 46 potential targets of arecoline were identified. Concurrently, 2,375 oral cancer-related targets were retrieved from GeneCards, OMIM, and TTD. Intersection analysis of these two target sets yielded 26 overlapping targets. PPI analysis revealed that TP53, IL6, SNAI1, and CASP3 occupied central positions in the network, exhibiting extensive interactions with other target proteins. Enrichment analysis comprehensively elucidated the molecular functions, biological processes, cellular components, and associated pathways of these overlapping targets. Further screening using Cytoscape software identified four core targets: TP53, TNF, IL6, and CASP3. Immune infiltration analysis indicated that the expression levels of TP53, TNF, IL6, and CASP3 in oral cancer tissues were positively correlated with the infiltration levels of immune cells, including CD8 + T cells, Th1 cells, NK cells, and macrophages. Molecular docking experiments demonstrated strong binding activities between arecoline and TP53, IL6, and CASP3, while TNF also exhibited moderate binding affinity. Dynamic simulation further verified the stable binding of arecoline to TP53, TNF, IL6 and CASP3. Arecoline may induce oral cancer by acting on core targets including TP53, TNF, IL6, and CASP3, which interfere with normal cellular growth regulation, inflammatory responses, and apoptotic mechanisms. Therapeutic strategies targeting TP53, TNF, IL6, and CASP3 may represent novel research directions for clinical diagnosis and treatment of oral cancer.

16Potent LeuBAT inhibitors designed in silico as next-generation duloxetine analogs for enhanced major depressive disorder treatment.PubMed

Mehdi Yoosefian, Hedieh Bayramzadeh, Kasim Sakran Abass, et al.
Major Depressive Disorder (MDD), a leading global health challenge, urgently requires advanced therapeutics to mitigate its widespread impact. In this study, a series of duloxetine (DLX) analogs were designed and evaluated using a comprehensive in silico workflow incorporating quantum chemical calculations, ADMET profiling, molecular docking, and molecular dynamics (MD) simulations. Density Functional Theory (DFT) calculations at the B3LYP/6-311G level were performed to assess electronic properties such as the HOMO-LUMO energy gap, dipole moment, electronegativity, and chemical softness. Among the designed compounds, DLX48 demonstrated superior quantum descriptors while retaining the electronic characteristics of the parent molecule. ADMET predictions using ADMETlab 3.0 and ProTox-II revealed that DLX48 complies with major drug-likeness rules (Lipinski, Pfizer), exhibits improved aqueous solubility (Log S = - 3.21), optimal lipophilicity (Log P = 2.87), and shows no predicted hepatotoxicity or genotoxicity. Molecular docking against the LeuBAT (Δ13 mutant) transporter revealed a significant increase in binding affinity for DLX48 (-12.45 kcal/mol), with an inhibition constant (Ki) of 742.09 pM-indicating markedly enhanced target engagement compared to DLX. Long-timescale MD simulations (300 ns) confirmed the thermodynamic stability and favorable dynamic behavior of the DLX48-LeuBAT complex, supported by lower RMSD/RMSF values, persistent hydrogen bonding, reduced solvent exposure, and constrained conformational fluctuations. Collectively, these in silico findings nominate DLX48 as a promising central nervous system (CNS)-active lead compound with enhanced pharmacological efficacy and a reduced toxicity profile, warranting further preclinical investigation for the treatment of depression and anxiety disorders.
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