Journal of Computer-Aided Molecular Design最新文献

Accurately predicting polymer density from SMILES strings remains challenging due to the small size, high noise, and chemically diversity of typical datasets. We introduce LiteBoost, a deliberately minimalist gradient boosting model that employs shallow, three-level symmetric trees and exposes only two tunable hyperparameters (n_estimators and learning_rate). Using a curated dataset of 613 polymers, we benchmark LiteBoost against ExtraTrees, XGBoost, LightGBM, and CatBoost, optimizing each with 100–1000 Optuna trials and evaluating performance across seven complementary metrics: R², RMSE, MAE, median AE, MAPE, maximum error, and explained variance. LiteBoost achieves a MAE of 0.031 g/cm³, RMSE of 0.062 g/cm³, R² of 0.81, and MAPE of 3.03%, all within 2–3% of the best-in-class CatBoost and XGBoost scores and well within the bounds of experimental uncertainty. Crucially, it does so with orders-of-magnitude fewer hyperparameters. These results demonstrates that a streamlined boosting model can rival heavyweight ensembles in accuracy while dramatically reducing tuning effort, computational cost, and interpretability barriers. LiteBoost is thus a practical first-line surrogate model for high-throughput polymer screening and inverse-design workflows where speed, robustness, and transparency are as critical as raw predictive power.

Deep generative models may detect novel compounds with favourable features, exhibiting chemical design potential. Traditional single-stage variational autoencoders (VAEs) lack validity, uniqueness, and biologically meaningful distribution alignment. It is difficult to represent global molecular architecture and chemical properties in a single latent representation. To overcome these challenges, we offer a multi-stage VAE system that encodes and decodes molecular representations in sequence. Improvements to latent space retain structural integrity while also adding innovation and distinction. Validity, originality, novelty, Fréchet ChemNet Distance (FCD), and KL divergence are used to validate the methodology with ChEMBL and polymer datasets. The bioefficacy of EGFR inhibitors is evaluated using computational Chemprop-based QSAR models. We offer adaptive fine-tuning strategies for the inner-layer (IL) and outer-layer (OL) to improve generating accuracy. IL adaptability is most suited to active compounds. Quantitative evaluations indicate consistent gains in validity, novelty, and biological activity over strong baselines (for example, MoLeR and RationaleRL). We give MNIST tests that confirm the hierarchical training method’s stability but not its scalability beyond molecular tasks, ensuring cross-domain applicability. For generative drug discovery, hierarchical latent models with a multi-stage VAE are advised.

Quantum-mechanical (QM) methods were applied to compute the relative binding energies of a set of structurally similar alkaline phosphatase (AP) inhibitors, using human placental AP (PLAP) as a model AP. The theoretical binding affinities were compared with their corresponding experimental inhibitory potencies. The calculated interaction energies reproduced the experimental activity order, showing linear correlations between QM relative binding energies and experimental pIC₅₀ values with coefficients of determination R² = 0.86–0.97. Examination of the binding interactions for the test inhibitors revealed that the AP inhibitory activity is determined by the catechol group and the benzimidazole/imidazole moieties of the ligands. The studied compounds formed protein-ligand complexes inside the active site of PLAP, suggesting they are competitive inhibitors. The present theoretical results are expected to be useful in developing new potent AP inhibitors. The employed computational approach for estimating QM protein − ligand interaction energies is proposed as a suitable drug design tool for predicting reliable QM relative binding affinities of structurally related compounds.

Pakistan currently holds the second-highest prevalence rate of Hepatitis C virus (HCV) globally. It makes it crucial to continuously monitor the circulating genotypes in the population, especially among the people who inject drugs (PWIDs), as they pose a significant risk of spreading new genotypes in the population. To address this issue, we identified the circulating HCV genotypes among PWIDs and non-PWIDs through Next Generation Sequencing (NGS). Additionally, a multi-epitope vaccine was designed through an immunoinformatic approach using NGS and Sanger sequencing results. The study indicated genotype 3a as the most prevalent genotype among the 61 HCV cases tested through NGS, followed by genotype 1a. The non-allergic and highly antigenic epitopes from both MHC Class-I and Class-II epitopes were retreived from non-structural proteins. Furthermore, B-cell epitopes were retrieved from the E2 protein. The selected epitopes showed 88.26% population coverage rate. Based on large conformational simulation analysis from NMSims, four best constructs suitable for vaccine design were further evaluated for their binding energies through all-atom molecular dynamics simulations and the MMGBSA. One of the constructs showed a low binding energy value with MHC, indicating its potential as a vaccine candidate. However, further experimental work is required to determine its efficacy and safety profile. This research emphasizes the promise of combining multiepitope vaccine design advanced computational methods to accelerate and improve vaccine development thereby filling a crucial gap in the fight against rising antibiotic resistance.

Graphical abstract

FYN, a member of the Src family kinases (SFKs) and a non-receptor tyrosine kinase, plays a critical role in signal transduction within the nervous system and is instrumental in the activation and development of T lymphocytes. While the biological significance of FYN kinase in various cellular processes is well recognized, its potential as a therapeutic target remains largely unexplored. In this study, we investigated the potential of natural products (NPs) as preferential inhibitors of FYN kinase. A library of over 3500 NPs was screened for binding affinity with FYN kinase (PDB: 2DQ7) using XGlide docking simulations. The fourteen NPs with the highest docking scores were selected for further analysis. Their interactions with FYN kinase were evaluated through MM-GBSA calculations, and ADMET profiling was performed using SwissADME and pkCSM tools to assess pharmacokinetic properties. Molecular dynamics (MD) simulations using Desmond further confirmed the stability of FYN-NP complexes in solvent environments. Of the top fourteen NPs, only oroxin A demonstrated favorable drug-like properties and sustained stable binding to FYN kinase, as evidenced by MD simulations. Moreover, in vitro kinase inhibition assays revealed that oroxin A exhibited dose-dependent inhibition of FYN kinase. Additionally, C. elegans viability assays confirmed its low toxicity. Moreover, cross-docking revealed that although oroxin A binds to multiple SFKs due to conserved ATP binding pocket, it displayed stronger binding toward FYN, suggesting binding preference over FYN. This study provides a comprehensive evaluation of NPs as potential FYN kinase inhibitors and identifies oroxin A as a natural compound with preliminary evidence of FYN inhibition, warranting further validation.

Despite the widespread use of Grossamide-containing plants in traditional medicine and its documented anti-inflammatory and metabolic regulatory properties, this lignanamide's potential as an antidiabetic agent remains unexplored. Current α-glucosidase inhibitors like acarbose suffer from poor patient compliance due to severe gastrointestinal side effects, creating an urgent need for better-tolerated alternatives. This study investigated whether Grossamide’s unique structural features and established bioactivities could translate into clinically relevant carbohydrase inhibition. Through integrated computational and experimental approaches, we demonstrate that Grossamide exhibits potent dual inhibition of α-amylase (IC₅₀: 44.4 ± 5 μM) and α-glucosidase (IC₅₀: 72 ± 5 μM), showing 50% and 33% lower IC₅₀ values than acarbose (89 and 108 μM, respectively) and comparing favorably to natural inhibitors like quercetin (> 200 μM) while approaching potencies of semi-synthetic derivatives, though not reaching synthetic drug levels (0.2–1 μM). Molecular docking revealed distinct binding modes for each enzyme, with preferential α-amylase engagement potentially reducing side effects associated with excessive α-glucosidase inhibition. Extensive molecular dynamics simulations (100 ns) confirmed binding stability and identified a persistent hydrogen bond network with GLN63 (91% occupancy) as critical for α-amylase inhibition, while α-glucosidase binding involved dynamic interactions across multiple subsites. MM/GBSA calculations revealed strong binding affinities driven predominantly by van der Waals forces, contrasting with the electrostatic-dependent binding of current clinical inhibitors. Comprehensive ADMET profiling predicted acceptable drug-likeness despite the compound's large size, with favorable safety parameters supporting therapeutic development. These findings establish Grossamide as a promising scaffold for developing dual-action antidiabetic agents and demonstrate how computational drug design can identify new therapeutic applications for known natural products, potentially accelerating the drug discovery timeline by repurposing compounds with established safety profiles.

The overexpression or activation of C-terminal Src kinase (CSK) has been recognized as a pivotal factor in the progression of hepatocellular carcinoma (HCC), positioning CSK as a promising therapeutic target. Despite this potential, no CSK-specific inhibitors have been developed for HCC treatment to date. Addressing this gap, our study established a robust virtual screening protocol that integrates energy-based screening techniques with machine learning methodologies. Through this systematic approach, we identified a novel compound, 6, exhibiting potent CSK inhibitory activity, as evidenced by an IC₅₀ value of 675 nM in a homogeneous time-resolved fluorescence (HTRF) bioassay. Notably, this compound demonstrated significant growth inhibition in Huh-7 and Huh-6 cell lines, along with the suppression of clone formation. To elucidate the underlying mechanism, we conducted molecular dynamics simulations, which revealed critical binding interactions between compound 6 and CSK. Specifically, residues Phe333 and Met269 were found to play essential roles in mediating these interactions, providing valuable insights into the compound’s mode of action.

Antimicrobial resistance (AMR) remains a global health crisis, necessitating the development of novel therapeutics against multidrug-resistant pathogens. In this study, ten (10) hybrid imine-benzalacetophenone derivatives (7a–7j), incorporating pyridine and thiophene scaffolds, were synthesized and structurally characterized using FTIR, ¹H-NMR, LC–MS, and elemental analysis. In vitro, antimicrobial screening demonstrated that compounds 7c and 7j displayed consistent and potent activity across Gram-positive and Gram-negative bacterial strains and fungal pathogens, with compound 7c achieving MICs as low as 25 µg/mL. Compound 7c exhibited significant antitubercular activity with 96% inhibition at 25 µg/mL against Mycobacterium tuberculosis H37Rv. A deep learning-based QSAR model, developed using a fully connected feedforward neural network trained on molecular descriptors (MolWt, LogP, TPSA, H-bond donors/acceptors, etc.), yielded predicted pMIC values closely matching experimental trends. SHAP analysis confirmed the multivariate contribution of key descriptors, validating the model’s interpretability despite dataset constraints. SwissADME-based pharmacokinetic profiling confirmed high gastrointestinal absorption, low PAINS alerts, and compliance with Lipinski and Veber rules for drug-likeness. Compounds 7c and 7j demonstrated balanced lipophilicity, low skin permeability, and favourable ADMET characteristics, aligning with their firm biological profiles. Molecular docking showed strong binding affinities for 7c (− 11.55 kcal/mol with CYP51) and 7j (− 9.97 kcal/mol with InhA), with multiple hydrogen bonds and hydrophobic interactions at catalytically relevant sites. These interactions were consistent with observed antimicrobial profiles. These docking predictions were validated by 200 ns molecular dynamics simulations, which confirmed the structural stability of 7c and 7j in complex with CYP51, InhA, PBP2a, and DNA Gyrase B. RMSD and RMSF trajectories, indicated stable ligand retention and minimized flexibility at the binding interface, particularly for 7c with CYP51 and InhA, and for 7j with DNA Gyrase B. These results support 7c and 7j as promising lead candidates with dual antimicrobial potential, favourable drug-like properties, and broad-spectrum activity profiles.

The widespread use of pesticides such as deltamethrin (a pyrethroid) and acetamiprid (a neonicotinoid) has sparked concerns regarding their effects on human health, particularly their potential role in carcinogenesis. This study investigated the cytotoxic, molecular, and functional effects of these pesticides, individually and in combination, on the MDA-MB-231 triple-negative breast cancer (TNBC) cell line. This model was chosen to specifically investigate estrogen recpetor (ER)-independent mechanisms due to its expression of targets such as aryl hydrocarbon receptor (AhR), peroxisome proliferator-activated receptor gamma (PPARγ), and G protein-coupled estrogen receptor (GPER); however, it does not reflect normal mammary cell responses. Cytotoxicity was assessed via XTT assays, migration was analyzed using wound-healing assays, and gene expression changes in AhR, PPARγ, and Caspase-3 were measured using RT-qPCR. Molecular docking was performed to predict pesticide-protein interactions, and in silico toxicity assessments using ProTox-II supplemented the in vitro results by predicting toxicity profiles relevant to public health. Both pesticides exhibited dose-dependent cytotoxicity, and their combination produced an additive effect on cell viability. Importantly, suppression of cell migration and downregulation of AhR and PPARγ expression reflected toxic stress responses at high pesticide concentrations, rather than therapeutic or anti-cancer potential. While apoptosis-related gene expression (Caspase-3) was increased, this effect did not reach statistical significance. Molecular docking supported strong interactions with key pathways related to xenobiotic metabolism and apoptosis. These findings emphasize that, at high and non-environmentally relevant concentrations, deltamethrin and acetamiprid induce additive cytotoxic effects and disrupt molecular processes in a mechanistic cancer model. The results highlight the need for further investigation using normal cell systems and environmentally relevant exposures to clarify real-world risk and biological mechanisms, and should not be interpreted as evidence of therapeutic activity. This study underscores the mechanistic relevance of pesticide exposure in environmental toxicology rather than any potential therapeutic application.

Fluoxastrobin (FLUO) is a fungicide from strobilurin family used widely worldwide. The use of FLUO pesticide is on the rise and this phenomenon is accompanied by a series of concerns such as endocrine disruption. In order to determine the potential toxic effects of FLUO, cell culture, gene expression and molecular docking assays were conducted as it is crucial to determine the interaction between chemicals and nuclear receptors in order to estimate and understand the impact of the chemical. This study analyzed the quantum properties of FLUO at the molecular quantum mechanical level using Density Functional Theory (DFT) with the B3LYP/6-311 + + G(d, p) and cc-pVDZ basis sets including the HOMO-LUMO energy gap, chemical reactivity descriptors, molecular electrostatic potential (MEP) surface calculation. In order to investigate molecular characteristics, topological (AIM, RDG) and Natural Bonding Orbitals (NBO) investigations were conducted. Molecular docking studies were performed with the title compound in the active sites of the proteins selected because of their role in xenobiotic metabolism. The docking result was determined to be a significant factor in bioactivity, a finding that is corroborated by the cytotoxic analysis of the FLUO compound. Density Functional Theory (DFT) computations are used to support molecular docking analysis. Toxicity of FLUO was tested on MDA-MB-231 cells using XTT and wound healing assays. IC50 value of FLUO was determined as 6,9 µg/ml. The impact of FLUO exposure at molecular level was assessed using qRT-PCR by determining the expression levels of PPARy, AhR and PXR genes where no statistically significant change was found.