JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
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2026
·Vol. 40
·期 1
·52
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IF 3.1
Lu JiaHao,Zhao ChenHao,Qiu YingQI,Shen Li-Qun,Zhu Hua,Zhang Miao
Survivin, a multifunctional regulator of mitosis and apoptosis, plays a central role in cancer progression and therapy resistance, making it an attractive target for anticancer drug development. In this study, a series of 4,6-diphenyl-3-cyanopyridine derivatives were designed and synthesized as potential survivin inhibitors through an integrated strategy combining 3D-QSAR modeling, molecular docking, molecular dynamics simulations, and biological evaluation. The CoMFA and CoMSIA models established reliable structure–activity relationships and provided contour-map-based guidance for rational molecular optimization. Newly designed derivatives displayed enhanced antiproliferative effects against melanoma cells, and computational analyses revealed that the most promising compound showed stable and preferential binding within the BIR domain of survivin, particularly in its dimeric form. These findings demonstrate the effectiveness of contour-guided optimization in discovering novel survivin-targeting scaffolds and highlight 4,6-diphenyl-3-cyanopyridine derivatives as promising leads for further anticancer drug development. Future studies will focus on improving selectivity, clarifying the inhibition mechanism at the molecular level, and evaluating in vivo efficacy.
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PEST MANAGEMENT SCIENCE
·
2026
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IF 4.2
XiGuang Wang,XinYi Huang,YanJun Li,ShengHe Ye,GuoLiang Wu,JingYa Yuan,MingWei Gao,JiaYing Liu,LiYan Song,QingWei Tan,QiJian Chen,JiangTao Gao,BinBin Huang
BACKGROUND Fusaric acid (FA), a non-host-selective toxin with antifungal and insecticidal activities, has attracted attention as a promising lead structure for developing novel agrofungicides. This study aimed to design and synthesize FA derivatives with improved antifungal activity and reduced phytotoxicity, and to investigate their antifungal mechanism and structure–activity relationships. RESULTS A series of FA derivatives were synthesized and evaluated against six major plant pathogenic fungi, including Magnaporthe oryzae . Several derivatives showed enhanced antifungal activity compared with the previously identified scaffold H52 , and 10 compounds completely inhibited M. oryzae at 100 μg mL −1 under in vitro conditions. The most active derivatives exhibited half-maximal effective concentration (EC 50 ) values of 6.09–9.84 μg mL −1 . Phytotoxicity assays showed that compounds A6 , A10 , A12 , B4 , B6 , and B7 had safety profiles comparable to the commercial fungicide azoxystrobin. Compound B4 further demonstrated concentration-dependent protective activity against rice blast under pot conditions, reducing the disease index from approximately 66.7 in the untreated control to about 14.8 at the highest tested concentration. Mechanistic studies revealed severe hyphal deformation, cell wall disruption, intracellular leakage, and reactive oxygen species (ROS) accumulation following B4 treatment. A comparative molecular field analysis-based three-dimensional quantitative structure–activity relationship (3D-QSAR) model exhibited strong predictive performance ( q 2 = 0.69, r 2 = 0.992), indicating reliable structure–activity relationships. Contour map analysis suggested that bulky substituents near the core ring and electron-withdrawing groups in specific regions significantly enhance antifungal activity. CONCLUSION FA derivatives can be rationally optimized to improve antifungal activity, reduce phytotoxicity, and be effective in planta disease control, providing promising candidates and design strategies for next-generation agrofungicides. © 2026 Society of Chemical Industry.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2024
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IF 4.7
Xiulian Yang,Shaowei Wang,Yunbing Tang,Yingfen Ying,Yang Zhu,Congde Chen,Ren-shan Ge,Miaoqing Liu
The use of salicylates as flavoring agents in food and beverages is common, but their potential to disrupt the endocrine system remains unclear. Human placental 3β-hydroxysteroid dehydrogenase 1 (h3β-HSD1) plays a role in progesterone synthesis and is the potential target. This study evaluated the inhibition of 13 salicylates on h3β-HSD1, structure-activity relationship (SAR) and compared with rat placental homolog r3β-HSD4. Salicylates inhibited h3β-HSD1, depending on carbon chain number in the alcohol moiety and the IC 50 values for hexyl, ethylhexyl, homomenthyl, and menthyl salicylates were 53.27, 15.78, 2.35, and 2.31 μM, as mixed inhibitors, respectively, while methyl to benzyl salicylates were ineffective at 100 μM. Interestingly, only hexyl salicylate inhibited r3β-HSD4 with IC 50 of 31.05 μM. Bivariate analysis revealed a negative correlation between IC 50 and hydrophobicity (LogP), molecular weight, heavy atoms, and carbon number in the alcohol moiety against h3β-HSD1. Docking analysis demonstrated that these salicylates bind to cofactor binding sites or between the steroid and cofactor binding sites. Additionally, 3D-QSAR showed distinct binding via hydrogen bond donors and hydrophobic regions. In conclusion, the inhibition of h3β-HSD1 by salicylates appears to be dependent on factors such as LogP, molecular weight, heavy atoms, and carbon-chain length and there is species-dependent inhibition sensitivity.
研究领域:
药理学
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毒理学
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内分泌学
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分子生物学
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CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Zhuohua Cao,Siyu Men,Zhenhua Li,Gang Liu,Qingying Su,Xinran Chen,Xianhua Che,Hanyong Jin
Organophosphate esters (OPEs) are widespread environmental contaminants increasingly recognized for their metabolic-disruption potential. However, systematic cross-structure comparisons of their inhibitory effects on human carboxylesterase 1 (hCES1), an enzyme involved in xenobiotic metabolism and lipid homeostasis, remain limited. Here, we established an OPE-centered cross-structure inhibition dataset for hCES1 using 25 structurally diverse organophosphate compounds, revealing a pronounced structure-dependent potency pattern across the series (IC 50 : 2.538 nM to > 600 μM). More potent inhibition was enriched among compounds bearing P=O motifs and aryl-containing substituents, although the overall activity pattern could not be explained by any single empirical structural label. To resolve the determinants underlying this stratification, we developed complementary QSAR models. The 2D-QSAR models captured global descriptor-level trends but showed only moderate predictive ability ( R 2 ≥ 0.918, q 2 ≥ 0.508), whereas the scaffold-based 3D-QSAR models (CoMFA and CoMSIA) offered a more spatially informative explanation of activity variation ( R 2 ≥ 0.947, q 2 ≥ 0.374, RMSE ≤ 0.420), indicating that steric, electrostatic, hydrophobic, and hydrogen-bonding effects jointly shape hCES1 inhibition. Molecular docking further showed that more potent aryl-rich compounds achieved broader hydrophobic occupancy and denser nonpolar contacts within the hCES1 catalytic cavity. Complementary quantum-chemical analyses indicated that the phosphorus center was the major electron-deficient site, while phosphorus-centered bonding environments and side-chain features contributed differently to electrophilic susceptibility and pocket recognition. Overall, hCES1 inhibition by organophosphate compounds can be interpreted within a layered SAR framework in which side-chain-mediated cavity recognition and phosphorus-centered electronic effects jointly shape inhibitory activity.
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JOURNAL OF HAZARDOUS MATERIALS
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2024
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IF 12.2
He Zhu,Chentao Ding,Yunbing Tang,Jingyi Zheng,Shaowei Wang,Zhongyao Ji,Yang Zhu,Ren-shan Ge,Huitao Li
Parabens are preservatives used in personal care products, cosmetics, and pharmaceuticals. Steroid 5α-reductase 1 (SRD5A1) catalyzes the conversion of testosterone to dihydrotestosterone and is present in the brain, contributing to neurosteroid production. This study aimed to assess the effects of nine paraben preservatives on SRD5A1 in human SF126 glioblastoma cell and rat brain microsomes, particularly focusing on dihydrotestosterone production in SF126 cells. The results showed that methyl, ethyl, propyl, butyl, hexyl, heptyl, nonyl, phenyl, and benzyl paraben inhibited human SRD5A1, with nonylparaben having the strongest effect (7.59 μM). Additionally, kinetic analysis indicated that parabens acted as mixed/noncompetitive inhibitors, leading to a significant decrease in dihydrotestosterone production in SF126 cells. While rat SRD5A1 exhibited lower sensitivity to parabens, docking analysis revealed that parabens bind to the NADPH-binding site of both human and rat SRD5A1. In conclusion, these results highlight the inhibitory effects of paraben preservatives on SRD5A1 and elucidate their binding mechanisms, underscoring their role in hormone production.
研究领域:
药理学
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毒理学
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生物化学
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分子生物学
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神经科学
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MOLECULES
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2023
·Vol. 28
·期 4
·1911
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IF 4.6
Xiaocui Wu,Guishan Lin,Wengui Duan,Baoyu Li,Yucheng Cui,Bo Cen,Fuhou Lei
Twenty-two novel longifolene-derived diphenyl ether-carboxylic acid compounds7a–7vwere synthesized from renewable biomass resources longifolene, and their structures were confirmed by FT-IR,1H NMR,13C NMR, and HRMS. The preliminary evaluation of in vitro antifungal activity displayed that compound7bpresented inhibition rates of 85.9%, 82.7%, 82.7%, and 81.4% againstAlternaria solani, Cercospora arachidicola,Rhizoctonia solani,andPhysalospora piricola, respectively, and compound7lpossessed inhibition rates of 80.7%, 80.4%, and 80.3% againstR. solani,C. arachidicola,P. piricola, respectively, exhibiting excellent and broad-spectrum antifungal activities. Besides, compounds7fand7ashowed significant antifungal activities with inhibition rates of 81.2% and 80.7% againstA.solani, respectively. Meanwhile, a reasonable and effective 3D-QSAR mode (r2= 0.996,q2= 0.572) has been established by the CoMFA method. Furthermore, the drug-loading complexes7b/MgAl-LDHwere prepared and characterized. Their pH-responsive controlled-release behavior was investigated as well. As a result, complex7b/MgAl-LDH-2exhibited excellent controlled-releasing performance in the water/ethanol (10:1, v:v) and under a pH of 5.7.Keywords:longifolene;hydrotalcite;antifungal activity;3D-QSAR;controlled-releasing
研究领域:
有机化学
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药学
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材料科学
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2012
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IF 2.823
Jun Shang,Wei-Min Wang,Yong-Hong Li,Hai-Bin Song,Zheng-Ming Li,Jian-Guo Wang
Acetohydroxyacid synthase (AHAS; EC 2.2.1.6) is an important bioactive target for the design of environmentally benign herbicides. On the basis of previous virtual screening, 50 asymmetric aryl disulfides containing [1,2,4]triazole groups were synthesized and characterized by 1H NMR, HRMS, and crystal structure. Compounds I-a, I-b, and I-p show Ki values of 1.70, 4.69, and 5.57 μM, respectively, for wild type Arabidopsis thaliana AHAS (AtAHAS) and low resistance against mutant type AtAHAS W574L. At 100 mg L–1 concentration, compounds I-a, II-a, and II-b exhibit 86.6, 81.7, and 87.5% in vivo rape root growth inhibition. CoMFA steric and electrostatic contour maps were established, and a possible binding mode was suggested from molecular docking, which provide valuable information to understand the key structural features of these disulfide compounds. To the authors' knowledge, this is the first comprehensive case suggesting that asymmetric aryl disulfides are novel AHAS inhibitors.
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ANALYTICA CHIMICA ACTA
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2018
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IF 5.123
Congmin Liu,Xiaowen Dou,Lei Zhang,Weijun Kong,Liu Wu,Yaping Duan,Meihua Yang
In the present study, molecular modeling and principle component analysis (PCA) were used to select appropriate haptens for group detection of triazine herbicides. Four new structures together with three reported triazine derivatives were chosen for the screening of immunizing and coating haptens . A total of 31 triazines coupled with a 3D-QSAR methodology were employed to investigate the relationship between antigen-antibody recognition and molecular structures, the results of which revealed that the antibodies may recognize triazines from the side of molecules with the distinguishing atom and a steric volume matching with the spatial structure of antibodies. Finally, a broad-specificity heterologous immunoassay was developed for determining 10 triazine herbicides in ginger, where the detection limits were 2.5–15.1 μg kg −1 and recoveries were 67.9–102.6%. This study may broaden insight into triazine-antibody interactions and benefit designing novel performance-enhanced antibodies. The developed immunoassay can be further used for triazine detection in other complicated matrices.
研究领域:
分析化学
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分子生物学
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环境科学
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农业化学
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ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2025
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IF 6.1
Jianmin Sang,Kangjian Sang,Xuewei Ding,Zhengzheng Wang,Lieying Fan
Organochlorine fungicides are widely used in agriculture and personal care products for their antimicrobial properties, but growing evidence suggests they may act as endocrine disruptors. This study investigated the inhibitory effects of seven organochlorine fungicides on 3β-hydroxysteroid dehydrogenase (3β-HSD) using in vitro assays, molecular docking, and 3D-QSAR analysis. Five fungicides significantly inhibited human 3β-HSD2 in KGN cells, with dichlone (DCN) being the most potent (IC 50 = 1.97 µM). In contrast, only four fungicides affected rat 3β-HSD1, with triclosan (TCS) exhibiting the strongest inhibition (IC 50 = 19.5 µM). Both human 3β-HSD2 and rat 3β-HSD1 were inhibited in a mixed manner, leading to reduced progesterone production in KGN cells. Molecular docking revealed interactions with the enzyme's steroid-active site. Inhibitory strength correlated with lipophilicity (LogP), topological polar surface area (tPSA), and binding energy (ΔG). Pharmacophore analysis identified hydrogen bond acceptor-lipid (HBA-lipid) and hydrophobic (HY) features as critical. These findings demonstrate that organochlorine fungicides disrupt gonadal steroidogenesis by inhibiting 3β-HSD, raising concerns about their potential adverse effects on reproductive health.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2026
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IF 5.2
Xiya Ren,Zhuoqi Chen,Chengshuang Pan,Yingfen Ying,Yang Zhu,Ren-shan Ge,Yi Liu
Salicylates (SEs) are a diverse group of compounds with wide-ranging applications and potential endocrine-disrupting properties. This study investigated how structural features of SEs govern their inhibition of human 3β-hydroxysteroid dehydrogenase 2 (h3β-HSD2) in KGN cells and rat testicular 3β-HSD1 (r3β-HSD1), assessing progesterone secretion. SE hydrophobicity and steric bulk strongly correlated with inhibitory potency [IC 50 range: ethylhexyl SE (20.93 μM) to aspirin (103.43 μM) for h3β-HSD2 or ethylhexyl SE (56.50 μM) to phenyl SE (143.01 μM) for r3β-HSD1] with mixed/noncompetitive inhibition. Notably, ethylhexyl, homomenthyl, and benzyl SEs significantly suppressed progesterone secretion in KGN cells at concentrations as low as 1 μM. Docking analysis suggested SE binding near NAD + /steroid sites. Bivariate correlation linked higher pIC 50 to higher hydrophobicity (LogP, apolar desolvation energy), 3D complexity (Fsp 3 , molecular volume), and steric feature (Sterimol L). 3D-QSAR identified key interaction regions (hydrophobic regions), with ethylhexyl SE engaging most regions, unlike aspirin. This study first combined experimental and in silico analysis of SE-3β-HSD interactions.
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BIOORGANIC CHEMISTRY
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2026
·
IF 5.1
Nianci Chen,He Zhu,Chuhang Chi,Yilin Xu,Yunbing Tang,Yingfen Ying,Ren-shan Ge
Benzalkonium chloride (BAC) disinfectants are widely used, but their potential to disrupt reproductive endocrine systems remains known. Human placental 3β-hydroxysteroid dehydrogenase 1 (h3β-HSD1) plays a key role in progesterone biosynthesis and is the potential target. This study investigates the inhibitory effects of 9 BACs on h3β-HSD1 and rat placental (r3β-HSD4) homolog. Kinetic analyses revealed h3β-HSD1 exhibited a Michaelis constant Km of 0.261 μM, while r3β-HSD4 showed similar Km (0.254 μM). Screening identified C12-C18 BACs as potent inhibitors (IC 50 : 1.15–20.43 μM for h3β-HSD1; 1.90–20.75 μM for r3β-HSD4), with mixed/noncompetitive inhibition confirmed by Lineweaver-Burk plots. A BAC mixture demonstrated antagonistic effects. Functional cell assays in JAr cells showed that C12-C18 suppressed progesterone biosynthesis, with potency influenced by membrane permeability and inhibitory strength. Structure-activity relationship (SAR) and 3D-QSAR models highlighted hydrophobicity, alkyl chain length as well as steric features as key determinants, validated by pharmacophore mapping. Molecular docking revealed conserved NAD + -binding interactions, with C18 exhibiting the highest affinity via hydrogen bonds and hydrophobic contacts as well as van der Waals. Molecular dynamics simulations confirmed stable enzyme-ligand complexes. Pharmacokinetics prediction profiling indicated variable solubility (C12 > C14 > C16 = C18). These findings elucidate BAC-mediated endocrine-disrupting mechanisms and support structure-based optimization of inhibitors.
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