Youngjin Choi

Breast cancer is known as a frequently diagnosed malignancy in women. Over 70% of cases express estrogen receptor α (ERα). The activation of ERα promotes tumor proliferation and progression. Furthermore, mutations in ERα lead to acquired resistance against standard endocrine therapies such as tamoxifen. The induced resistance posed a significant clinical challenge in metastatic breast cancer. In this study, research for identifying novel, naturally derived compounds to inhibit the Y537S‐mutated ERα was conducted using in silico methods supported by an in vitro cytotoxicity screen. Molecular docking and molecular dynamics simulations served as the primary in silico screening strategies. The top 2% of candidates were filtered from a docking screen of the IBS natural library composed of over 15,000 chemicals. From this group, 11 compounds were purchased and tested using a cell‐based cytotoxicity assay in MCF‐7 before advancing to detailed simulations. Five candidates were then advanced to 150 ns MD simulations. A post‐MD analysis followed, including MM‐PBSA binding free energy calculations and principal component analysis (PCA). The phytochemical ibs‐04156 was identified as the most promising overall candidate, predicted to maintain consistent stability across both the wild‐type and Y537S‐mutated ERα, while ibs‐18821 demonstrated potent mutant‐specific inhibition via an allosteric mechanism involving spatial deviations in distal helices H3 and H11. This result shows that mutated ERα can be potentially targeted by bioactive phytochemical scaffolds found through molecular modeling, presenting a potential therapeutic strategy for metastatic breast cancer resistant to therapies such as tamoxifen.

Autophagy-mitophagy pathways are essential for regulating immune homeostasis. However, their contribution to population-level chronic low-grade systemic inflammation (SI) remains unclear. The objective was to investigate the association between variation in the genes related to the autophagy-mitophagy pathways and SI, and to examine whether lifestyle factors modify this relationship. We conducted genome-wide association studies and gene-set enrichment analyses using data from the Korean Genome and Epidemiology Study (KoGES, n = 28,102) and UK Biobank (UKBB, n = 343,892). SI was defined as an elevated white blood cell count or high-sensitivity C-reactive protein. Using Core Longevity State Vectors (CLSVs)—gene sets representing immune-longevity pathways derived from comparative transcriptomic analysis—we tested six pathways and constructed a weighted genetic risk score (GRS) from significant variants. Gene–lifestyle interactions were examined with respect to major dietary and lifestyle factors. Among six CLSVs, only CLSV-2 (mitophagy and autophagy) showed a significant association with SI (β = 0.425, p = 0.008). Six single nucleotide polymorphisms (SNPs) in autophagy-mitophagy genes (INPP5D, ATG16L1, ATG7, AP3S1, OPTN, and VPS33A) were associated with SI in KoGES (p < 5 × 10⁻⁵), and ten SNPs (genes selected in KoGES plus RAB7A, ATG12, VPS33A, BECN1) reached genome-wide significance in UKBB (p < 5 × 10⁻⁸). A higher GRS was associated with increased SI in both cohorts and was strongly associated with metabolic syndrome (MetS, OR = 1.91 in KoGES; OR = 1.62 in UKBB). SI was characterized by neutrophilia with relative lymphopenia. In UKBB, significant gene–lifestyle interactions were observed for diet, physical activity, smoking, and alcohol (p < 0.01). Favorable lifestyle factors reduced SI most effectively in individuals with protective genotypes. Among individuals with a high vegetable/fruit intake, SI prevalence was 35%, 36%, and 38% in the negative-, zero-, and positive-GRS groups, respectively, compared with 36%, 45%, and 48% in the low-intake groups. In conclusion, genetic variations in autophagy-mitophagy pathways specifically influence SI. Genetic predisposition substantially modifies the benefits of lifestyle, underscoring the importance of integrating genetic and lifestyle factors in understanding SI susceptibility.

Programmed death-ligand 1 (PD-L1) is a crucial immune checkpoint protein that tumors often exploit to evade immune surveillance. This study systematically screened a library of 1031 FDA-approved drugs using a high-throughput molecular dynamics approach to identify potential inhibitors targeting PD-L1. From this screening, five promising compounds—vorapaxar, delafloxacin, tenofovir disoproxil, pivmecillinam, and fursultiamine—showed significant binding affinities to PD-L1 and demonstrated cytotoxic activity against A549 lung tumor cells. These candidates were further evaluated through extended molecular dynamics simulations lasting up to 150 ns to assess their structural stability, residue fluctuations, and binding free energy. Among the identified compounds, pivmecillinam demonstrated the most favorable results, exhibiting stable binding interactions and a binding free energy of −18.01 kcal/mol, comparable to that of the known PD-L1 inhibitor BMS-1. These findings suggest that pivmecillinam has promising immunomodulatory potential and could serve as a candidate for further development in cancer immunotherapy. Overall, this study underscores the value of integrating high-throughput MD and experimental approaches for drug repositioning to identify novel therapeutic agents.

Myeong Kwan Kim, Sungjoon Cho, YoungJin Choi, and Dongju Jung. BSL 2025;31:49-58. https://doi.org/10.15616/BSL.2025.31.1.49

In this study, we investigated the inhibitory potential of 60 flavonoids from six distinct subgroups on the programmed cell death ligand 1 (PD-L1) dimer through molecular docking and dynamics simulations. Using AutoDock Vina for docking, the binding poses and affinities were evaluated, revealing an average binding affinity of −8.5 kcal/mol for the flavonoids. Among them, ginkgetin exhibited the highest binding free energy of −46.73 kcal/mol, indicating a strong interaction with PD-L1, while diosmin followed closely, with −44.96 kcal/mol. Molecular dynamics simulations were used to further elucidate the dynamic interactions and stability of the flavonoid–PD-L1 complexes, with the analyses showing minimal root mean square deviation (RMSD) and favorable root mean square fluctuation (RMSF) profiles for several compounds, particularly formononetin, idaein, and neohesperidin. Additionally, contact number and hydrogen bond analyses were performed, which highlighted ginkgetin and diosmin as key flavonoids with significant binding interactions, evidenced by their stable conformations and robust molecular interactions throughout the simulations. Ultimately, a cell-based assay confirmed their ability to inhibit the proliferation of cancer cells. These results, validated through cell-based assays, indicate that the strategy of identifying natural compounds with anticancer activity using computational modeling is highly effective.

Oxidative stress is associated with insulin resistance and secretion, and antioxidant systems are essential for preventing and managing type 2 diabetes (T2DM). This study aimed to explore the polygenic variants linked to oxidative stress and the antioxidant system among those associated with T2DM and the interaction of their polygenic risk scores (PRSs) with lifestyle factors in a large hospital-based cohort (n = 58,701). Genotyping, anthropometric, biochemical, and dietary assessments were conducted for all participants with an average body mass index of 23.9 kg/m². Genetic variants associated with T2DM were searched through genome-wide association studies in participants with T2DM (n = 5383) and without T2DM (n = 53,318). The Gene Ontology database was searched for the antioxidant systems and oxidative stress-related genes among the genetic variants associated with T2DM risk, and the PRS was generated by summing the risk alleles of selected ones. Gene expression according to the genetic variant alleles was determined on the FUMA website. Food components with low binding energy to the GSTA5 protein generated from the wildtype and mutated GSTA5_rs7739421 (missense mutation) genes were selected using in silico analysis. Glutathione metabolism-related genes, including glutathione peroxidase (GPX)1 and GPX3, glutathione disulfide reductase (GSR), peroxiredoxin-6 (PRDX6), glutamate–cysteine ligase catalytic subunit (GCLC), glutathione S-transferase alpha-5 (GSTA5), and gamma-glutamyltransferase-1 (GGT1), were predominantly selected with a relevance score of >7. The PRS related to the antioxidant system was positively associated with T2DM (ORs = 1.423, 95% CI = 1.22–1.66). The active site of the GASTA proteins having valine or leucine at 55 due to the missense mutation (rs7739421) had a low binding energy (<−10 kcal/mol) similarly or differently to some flavonoids and anthocyanins. The PRS interacted with the intake of bioactive components (specifically dietary antioxidants, vitamin C, vitamin D, and coffee) and smoking status (p < 0.05). In conclusion, individuals with a higher PRS related to the antioxidant system may have an increased risk of T2DM, and there is a potential indication that exogenous antioxidant intake may alleviate this risk, providing insights for personalized strategies in T2DM prevention.

Rhizobium leguminosarum biovar trifolii TA-1, a kind of soil bacteria, produces cyclosophoraoses (Cys). Cyclosophoraoses contain various ring sizes with degrees of polymerization ranging from 17 to 23. Atrazine is a hardly-soluble herbicide that contaminates soil and drinking water, and remains in soil for a long time. To remove this insoluble contaminant from aqueous solutions, we have enhanced the solubility of atrazine by complexation with Cys. The complex formation of Cys and atrazine was confirmed using ¹H nuclear magnetic resonance (NMR), Fourier transform infrared (FT-IR) spectroscopy, differential scanning calorimetry (DSC), field emission scanning electron microscopy (FE-SEM), rotating frame nuclear overhauser spectroscopy (ROESY), and molecular modeling studies. The aqueous solubility of atrazine was enhanced 3.69-fold according to the added concentrations (20 mM) of Cys, compared to the 1.78-fold enhancements by β-cyclodextrin (β-CD). Cyclosophoraoses as an excellent solubility enhancer with long glucose chains that can effectively capture insoluble materials showed a potential application of microbial polysaccharides in the removal of hazardous hardly-soluble materials from aqueous solutions in the fields of biological and environmental industry.