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
·
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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高影响因子
WATER RESEARCH
·
2024
·
IF 11.4
Yandong Yang,Xiangkun Jiang,Yi Yang,Jia Wang,Yahui Zhao,Shanshan Lin,Jiao Qu,Christopher J. Martyniuk,Yuanhui Zhao,Chao Li
Liquid crystal monomers (LCMs) are a new class of emerging pollutants with high octanol-water partition coefficients; however, their transformation behavior and associated risk to environments with high organic matter content has rarely been reported. In this study, we investigated the photodegradation kinetics, mechanism, and toxicity variation of 23 LCMs on leaf wax models (e.g., organic solvents methanol and n-hexane). The order of the photolysis rates of these LCMs were biphenylethyne LCMs > phenylbenzoate LCMs > diphenyl/terphenyl LCMs under simulated sunlight, while the phenylcyclohexane LCMs were resistant to photodegradation. The phenylbenzoate and biphenylethyne LCMs mainly undergo direct photolysis, while the diphenyl/terphenyl LCMs mainly undergo self-sensitized photolysis. The main photolysis pathways are the cleavage of ester bonds for phenylbenzoate LCMs, the addition, oxidation and cleavage of alkynyl groups for biphenylethyne LCMs, and the cleavage/oxidation of chains attached to phenyls and the benzene ring opening for diphenyl/terphenyls LCMs. Most photolysis products remained toxic to aquatic organisms to some degree. Additionally, two quantitative structure-activity relationship models for predicting k obs of LCMs in methanol and n-hexane were developed, and employed to predict k obs of 93 LCMs to fill the k obs data gap in systems mimicking leaf surfaces. These results can be helpful for evaluating the fate and risk of LCMs in environments with high content of organic phase.
研究领域:
环境科学
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毒理学
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化学
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CHEMICO-BIOLOGICAL INTERACTIONS
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2024
·
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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SCIENCE OF THE TOTAL ENVIRONMENT
·
2024
·
IF 8.2
Yunhai Zhang,Haoran Mao,Qing Ma,Zihao Chen,Hao Wang,Anlin Xu,Yongjun Zhang
Numerous pharmaceuticals and personal care products (PPCPs) co-exist with various types of microplastics (MPs) in the environment, making it extremely hard to experimentally measure all their adsorption interactions. Thus, a precise prediction model is on demand. In this study, we combined the commonly used Dubinin-Astakhov (DA) model and the linear solvation energy relationships (LSERs) model to predict the adsorption capacity ( Q 0 ) and adsorption affinity ( E ) of MPs for PPCPs, including the key parameters of MP (specific surface area , oxygen-containing functional groups), and the Kamlet-Taft solvation parameters of organic contaminants. The model was validated with the experimental data of 8 PPCPs and 8 MPs (i.e. pristine and aged PE, PET , PS , PVC) plus some published adsorption data. This new model also indicated that the adsorption of PPCPs on those MPs was primarily governed by hydrophobic interaction and hydrogen bonding. The developed model can predict the adsorption of PPCPs onto MPs with a high accuracy and can also provide insights into the understanding of interaction forces in the adsorption process.
研究领域:
环境科学
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化学
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POLYMER
·
2026
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IF 5.1
Yongchao He,Hanzhao Kuang,Xiaoqing Liu,Hai Zheng,Yinhang Zhang,Xuan Wang,Yinghua Huang,Jinjing Tang,Feng Wang,Xudong Cui,Mingbo Yang,Hang Chen,Yanhao Huang
Coumarin oxime esters (COXEs) have received extensive attention for their outstanding photoinitiation performance, but their rational and efficient design is challenged by the vast combinatorial space of possible electron donor/acceptor substituents on the coumarin core. In this work, a two-dimensional quantitative structure-activity relationship (2D-QSAR) analysis of reported COXE structures was performed to examine the relationship between structural descriptors and photo-reactivity. It was revealed that the acceptor and donor of hydrogen bond (HA, DH), total energy ( E ), as well as energy gap ( E g ) strongly influence the absorption wavelength ( λ max ). In particular, the phenyl ring with electron-withdrawing substituents enhances the charge asymmetry of the adjacent N–O bond and induces a red shift in the absorption wavelength. As a result, a novel COXE, namely C-5, was rationally designed and synthesized with a pentafluorophenyl substituent. The λ max of C-5 was predicted by DFT and confirmed by the UV-vis spectrum to be 424 nm in acetonitrile. Meanwhile, C-5 exhibits strong absorption ( ε ) of about 8.66 × 10 3 M −1 cm −1 at 405 nm and shows rapid photobleaching under 405 nm irradiation. In addition, the GelNB system photocured by the C-5 photoinitiator enabled a polymerization conversion of about 25.8%, with an elastic modulus of 2878 MPa. This modulus is significantly higher than that of the samples cured by the LAP and Irgacure 2959. These results demonstrate that the 2D-QSAR-DFT collaborative design can identify and optimize novel COXE photoinitiators, thereby advancing the highly efficient, rational preparation of visible-light-active photoinitiators for visible-light photopolymerization.
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CHEMICO-BIOLOGICAL INTERACTIONS
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2026
·
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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FOOD AND CHEMICAL TOXICOLOGY
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2023
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IF 4.3
Miaomiao Xia,Jingyi Zheng,Sailin Chen,Yunbing Tang,Shaowei Wang,Zhongyao Ji,Ting Hao,Huitao Li,Linxi Li,Ren-shan Ge,Yi Liu
The use of alternative substances to replace bisphenol A (BPA) has been encouraged. The objective of this study was to evaluate the effects of BPA and 9 BPA alternatives on human and rat aromatase (CYP19A1) in human and rat placental microsomes . The results revealed that bisphenol A, AP, B, C, E, F, FL, S, and Z, and 4,4′-thiodiphenol (TDP) inhibited human CYP19A1 and bisphenol A, AP, B, C, FL, Z, and TDP inhibited rat CYP19A1. The IC 50 values of human CYP19A1 ranged from 3.3 to 172.63 μM and those of rat CYP19A1 ranged from 2.20 to over 100 μM. BPA alternatives were mixed/competitive inhibitors and inhibited estradiol production in BeWo placental cells. Molecular docking analysis showed that BPA alternatives bind to the domain between heme and steroid and form a hydrogen bond with catalytic residue Met374. Pharmacophore analysis showed that there were one hydrogen bond donor, one hydrophobic region, and one ring aromatic hydrophobic region. Bivariate correlation analysis showed that molecular weight , alkyl atom weight, and LogP of BPA alternatives were inversely correlated with their IC 50 values. In conclusion, BPA alternatives can inhibit human and rat CYP19A1 and the lipophilicity and the substituted alkyl size determines their inhibitory strength.
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RSC Advances
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2023
·Vol. 13
·期 16
·10523-10541
·
IF 3.9
Delong Wang,Min Li,Jing Li,Yali Fang,Zhijia Zhang
In an effort to exploit the bioactive natural scaffold 3,4-dihydroisoquinolin-1(2H)-one for plant disease management, 59 derivatives of this scaffold were synthesized using the Castagnoli–Cushman reaction. The results of bioassay indicated that their antioomycete activity against Pythium recalcitrans was superior to the antifungal activity against the other 6 phytopathogens. Compound I23 showed the highest in vitro potency against P. recalcitrans with an EC50 value of 14 μM, which was higher than that of the commercial hymexazol (37.7 μM). Moreover, I23 exhibited in vivo preventive efficacy of 75.4% at the dose of 2.0 mg/pot, which did not show significant differences compared with those of hymexazol treatments (63.9%). When the dose was 5.0 mg per pot, I23 achieved a preventive efficacy of 96.5%. The results of the physiological and biochemical analysis, the ultrastructural observation and lipidomics analysis suggested that the mode of action of I23 might be the disruption of the biological membrane systems of P. recalcitrans. In addition, the established CoMFA and CoMSIA models with reasonable statistics in the three-dimensional quantitative structure–activity relationship (3D-QSAR) study revealed the necessity of the C4-carboxyl group and other structural requirements for activity. Overall, the above results would help us to better understand the mode of action and the SAR of these derivatives, and provide crucial information for further design and development of more potent 3,4-dihydroisoquinolin-1(2H)-one derivatives as antioomycete agents against P. recalcitrans.
研究领域:
植物病理学
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药物化学
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分子生物学
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ENVIRONMENTAL POLLUTION
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2026
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IF 7.2
Xiaoxue Pan,Yuanyuan Gao,Le Tao,Chenguang Li,Xuesheng Zhang
Acute toxicity of 22 SPAs in two model aquatic species is detailedly studied. • BHT-Q, AO44S25, 4- t OP and DG possess high toxicity compared to the other SPAs. • ECOSAR data overestimate acute toxic effects of SPAs on selected aquatic species. • S w,l is the vital factor to determine the acute toxicity of SPAs. • They induce oxidative stress, damage tissues, and cause morphological deformation. In this paper, the acute toxicities to Scenedesmus obliquus and Danio rerio of 22 Synthetic phenolic antioxidants (SPAs) were investigated in detail. The half-effective concentrations ( EC 50 ) of 22 SPAs and half-lethal concentrations ( LC 50 ) of 14 SPAs were calculated by the corresponding toxicity effect curves. Results showed that except for 2,4-di- tert -butyl-1,4-benzoquinone (BHT-Q), an important intermediate of 2,6-di- tert -butyl-4-methylphenol (BHT), 4- tert -octylphenol (4- t OP) and dodecyl gallate (DG) with the relative EC 50 values of 2.35 and 2.53 mg/L were the most toxic among 22 SPAs. 4- t OP and DG also exhibited high toxicity, ranking within the top three to Danio rerio ( LC 50 : 0.53 and 0.57 mg/L, respectively), while the most toxic SPA was 4,4′-thiobis(6- tert -butyl- m -cresol) (AO44S25). Among these SPAs, they all belonged to toxic ∼ harmful category for green algae, and very toxic ∼ not harmful for zebrafish. Propyl gallate (PG) owned the highest EC 50 and LC 50 values, namely, PG with the lowest toxicity. Large discrepancy existed between the measured toxicity data and the predicted ones by ECOSAR. Two relatively robust quantitative structure-activity relationship (QSAR) models between EC 50 or LC 50 and eight typical structural parameters were built using linear-regression analysis. Water solubility ( S w,l ) was the vital parameter to determine the acute toxicities of the SPA congeners. Highly toxic BHT and 4- t OP possessed low water solubility and strong cell membrane penetration capacity. They could induce oxidative stress in green algal cells and cause damage to organelles such as mitochondria and chloroplasts, as well as morphological wrinkling and deformation of cells. These data can fill the toxicological knowledge gap for SPA congeners. Download: Download high-res image (259KB) Download: Download full-size image
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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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高影响因子
MOLECULES
·
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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危险品化学品经营许可证（带存储）