PHARMACEUTICAL RESEARCH
·
2003
·Vol. 20
·期 9
·1401-1408
·
IF 2.354
Wanchana Suchada,Yamashita Fumiyoshi,Hashida Mitsuru
Purpose . To develop a quantitative structure/activity relationship (QSAR) model for predicting drug-CYP 3A4 interactions.
Method . The inhibitory effect of 53 structurally diverse drugs on the metabolism of 7-benzyloxy-4-trifluoromethyl coumarin (BFC) by recombinant CYP 3A4 was evaluated using a rapid microtiter plate assay. For each drug, a total of 220 two-dimensional topological indices were calculated using Molconn-Z software. Using a genetic algorithm-based partial least squares (GA-PLS) method, the desired descriptors were automatically selected to maximize the predictability of the IC 50 values.
Results . The IC 50 values of the drugs tested ranged from 9 nM to 2 mM. Based on the GA-PLS method, five principal components derived from 20 Molconn-Z descriptors were found to be effective for QSAR modeling. Interestingly, these descriptors suggested that the molecular size would be an important factor in determining drug-CYP 3A4 interactions. In the leave-one-out prediction, the r
pred and the standard error of prediction ( s ) were 0.754 and 0.787, respectively. Even in an external validation, the predictions were in good agreement with experimental values ( r
pred = 0.744, s = 0.769, n = 9).
Conclusions . The proposed model, in which two-dimensional topological descriptors were used as molecular descriptors, was able to predict drug-CYP 3A4 interactions with reasonable accuracy.
研究领域:
药理学
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计算生物学
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药物化学
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DOI
PubMed
高影响因子
SAR AND QSAR IN ENVIRONMENTAL RESEARCH
·
2024
·
IF 2.3
Z. Ji,H. Chen,J.I. Zheng,J. Yan,H. Lu,J. He,Y. Zhu,S. Wang,L. Li,R.S. Ge,Y. Liu
Dithiocarbamate fungicides have been widely used in agricultural practices due to their effective control of fungal diseases, thereby contributing to global food security and agricultural productivity. In this study, the inhibitory potency of eight compounds on human and rat aromatase (CYP19A1) activity was evaluated. The results revealed that zineb exhibited the highest inhibitory potency on human CYP19A1 (IC50, 2.79 μM). Maneb (IC50, 3.09 μM), thiram (IC50, 4.76 μM), and ferbam (IC50, 6.04 μM) also demonstrated potent inhibition on human CYP19A1. For the rat CYP19A1, disulfiram (IC50, 1.90 μM) displayed the strongest inhibition followed by maneb (2.16 μM), zineb (2.54 μM), and thiram (6.99 μM). These dithiocarbamates acted as mixed/non-competitive inhibitors of human and rat CYP19A1. Dithiothreitol (DTT), a reducing agent, partially rescued thiram-mediated inhibition when incubated at the same. Moreover, positive correlations were observed between log P, topological polar surface area, molecular weight, and heavy atoms and IC50 values. 3D-QSAR analysis revealed the hydrogen bond acceptor and donor play critical roles in the binding of dithiocarbamates to human CYP19A1. In silico analysis showed that dithiocarbamates bind to the haem binding site, containing Cys437 residues. In conclusion, some dithiocarbamates potently inhibit human and rat CYP19A1 via interacting with haem-binding Cys437 residues.
研究领域:
药理学
·
生物化学
·
计算生物学
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DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
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2023
·
IF 3.8
Hongmei Li,Guimei Lin,Zhen Liang,Ying Li,Rong Zhang
Three novel antioxidant peptides MHW, YHW and FHW were designed by the analysis of 3D-QSAR. Two accurate CoMFA ( Q 2 = 0.886 and R 2 = 0.988) and CoMSIA ( Q 2 = 0.737 and R 2 = 0.955) models were established. The FTC assay showed that activities of the new peptides on lipid peroxidation is significantly better than that of the template molecule LHW. The results of erythrocyte hemolysis assay demonstrated that MHW, YHW and FHW significantly inhibited AAPH-induced erythrocyte hemolysis by scavenging free radicals at the cellular level. It caused the restoration of intracellular antioxidant enzyme (GSH, CAT and SOD) activities at an acceptable pace and the silencing of intracellular MDA formation. Furthermore, MTT toxicity assay showed that the novel antioxidant peptides had good biocompatibility and no cytotoxicity. Molecular docking and molecular dynamics simulations were used to investigate the molecular mechanism. The results showed that Ser363, Arg380, Asn414 and Arg415 residues played key roles in the antioxidant activity of MHW, YHW and FHW. And they mainly binded to the important residues of Keap1 protein stably by electrostatic force, van der Waals force, H-bonds and hydrophobic interactions, which can better fit the Kelch pocket structural domain of Keap1. Therefore, MHW, YHW and FHW had strong potential to interfere with Keap1-Nrf2 interaction and promoted the enzymatic expression of Nrf2-ARE downstream target pathway.
研究领域:
生物化学
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药物化学
·
分子生物学
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产品关联
DOI
高影响因子
JOURNAL OF STEROID BIOCHEMISTRY AND MOLECULAR BIOLOGY
·
2025
·
IF 2.5
Zhuoqi Chen,Chaochao Gong,Shaowei Wang,Han Lu,Yang Zhu,Ren-shan Ge,Yunbing Tang,Yingfen Ying
Benzophenone (BP) UV-filters have been extensively used for the prevention of UV-induced adverse effects in personal care products. Their potential to interfere with steroidogenesis in the female reproductive system remains uncertain. 17β-Hydroxysteroid dehydrogenase 1 (17β-HSD1) facilitates the conversion of estrone to estradiol, playing a key role in estrogen activation. This study delves into the effects of eleven BPs on human and rat 17β-HSD1, while also analysing the 3D-quntitative structure-activity relationship (3D-QSAR) and the underlying mechanisms. The inhibitory potency of inhibiting human placental 17β-HSD1 was found to be in the order of BP-2 (IC 50 , 11.42 μM) > BP-1 (14.17 μM) > BP-4 (49.05 μM) > BP-6 (63.49 μM) = BP-8 (63.46 μM) > others. BP-1 and BP-2 markedly inhibited estradiol secretion by human placental BeWo cells at ≥ 1 μM. In contrast, the inhibitory strength of suppressing rat ovarian 17β-HSD1 activity was found to be in the order of BP-2 (IC 50 , 13.33 μM) > BP-1 (15.09 μM) > BP-4 (22.68 μM) > BP-12 (31.12 μM) > BP (119.99 μM) > others. Mode action analysis revealed that these BP compounds acted as mixed inhibitors of both human and rat 17β-HSD1. The introduction of a 4-hydroxyl substitution in the benzene ring was found to markedly increase the inhibitory potency against human and rat 17β-HSD1. BP-1 and BP-2 demonstrated the ability to penetrate human BeWo cells and inhibit estradiol secretion at ≥ 1 μM. Docking analysis revealed that the 2-hydroxyl group of BP-1 and BP-2 forms a hydrogen bond with catalytic residue Ser142 of human 17β-HSD1. 3D-QSAR pharmacophore analysis showed that there are hydrophobic regions and hydrogen bond donor can interact with BPs. In conclusion, this study establishes that BP-2 is the most potent inhibitors of human 17β-HSD1 among the BPs under investigation, highlighting a significant difference in the structure-activity relationship.
研究领域:
生物学
·
医学
·
药理学
·
毒理学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2023
·
IF 8.8
Jin J. Li,Ya X. Yue,Jie F. Jiang,Sheng J. Shi,Hui X. Wu,Yuan H. Zhao,Fei F. Che
Antibiotics have received much attention owing to their ecotoxicity toward nontarget aquatic creatures. However, the mode of action (MOA) of toxicity against nontarget organisms is unclear in some aquatic organisms. In this study, the comparison of toxicities through interspecies correlations, excess toxicity calculated from toxicity ratio, and quantitative structure-activity relationship (QSAR) was carried out to investigate the MOAs for 14 antibiotics among Daphnia magna , Vibrio fischeri, and Pseudokirchneriella subcapitata . The results showed that interspecies toxicity correlations were very poor between any two of the three species for the 14 antibiotics. The toxicity ratio revealed that most antibiotics exhibited excess toxicity to algae and Daphnia magna but not to V. fischeri , demonstrating that some antibiotics share the same MOA, but some antibiotics share different MOAs among the three different levels of species. P. subcapitata was the most sensitive species, and V. fischeri was the least sensitive species. This is because of the differences in the biouptake and interactions of antibiotics with the target receptors between the three different trophic levels of the species. Molecular docking simulations suggested that the toxicity of antibiotics depends highly on their interactions with target receptors through hydrogen bonds , electrostatic or polar interactions, π bond interactions, and van der Waals forces . QSAR models demonstrated that hydrogen bonding and electrophilicity/nucleophilicity play key roles in the interaction of antibiotics with different receptors in the three species. The toxic mechanisms of antibiotics are attributed to the interactions between electrophilic antibiotics and biological nucleophiles , and hydrogen-bond interactions. These results are valuable for understanding the toxic mechanisms and MOA of the three different levels of species.
研究领域:
生态毒理学
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环境科学
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DOI
PubMed
高影响因子
ENVIRONMENTAL TOXICOLOGY AND CHEMISTRY
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2025
·
IF 2.8
Qi Qi,Wang Zhuang
In silico methods are increasingly important in predicting the ecotoxicity of engineered nanomaterials (ENMs), encompassing both individual and mixture toxicity predictions. It is widely recognized that ENMs trigger oxidative stress effects by generating intracellular reactive oxygen species (ROS), serving as a key mechanism in their cytotoxicity studies. However, existing in silico methods still face significant challenges in predicting the oxidative stress effects induced by ENMs. Herein, we utilized laboratory-derived toxicity data and machine learning methods to develop quantitative nanostructure-activity relationship (nano-QSAR) classification and regression models, aiming to predict the oxidative stress effects of five carbon nanomaterials (fullerene, graphene, graphene oxide, single-walled carbon nanotubes, and multi-walled carbon nanotubes) and their binary mixtures on Scenedesmus obliquus cells. We constructed five nano-QSAR classification models by combining zeta potential (ζP) with the C4.5 decision tree, support vector machine, artificial neural network, naive Bayes, and K-nearest neighbor algorithms. Moreover, we constructed three classification models by integrating the features including ζP, hydrodynamic diameter (DH), and specific surface area (SSA) with the logistic regression, random forest, and Adaboost algorithms. The Accuracy, Recall, Precision and harmonic mean of Precision and Recall (F1-score) values of these models were all higher than 0.600, indicating an excellent performance in distinguishing whether CNMs have the potential to generate ROS. In addition, using the ζP, DH, and SSA descriptors, we combined decision tree regression, random forest regression, gradient boosting, and the Adaboost algorithm, and successfully constructed four nano-QSAR regression models with applicable application domains (all training and testing data points lie within 95% confidence intervals), goodness-of-fit (Rtrain2 ≥ 0.850), and robustness (cross-validation R2 ≥ 0.650) as well as predictive power (Rtest2 ≥ 0.610). The method developed would establish a fundamental basis for more precise evaluations of ecological risks posed by these materials from a mechanistic standpoint.
研究领域:
环境毒理学
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计算生物学
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纳米科学
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产品关联
DOI
PubMed
高影响因子
CHEMOSPHERE
·
2019
·
IF 5.108
Zhiwen Cheng,Qincheng Chen,Frederick W. Pontius,Xiaoping Gao,Yujia Tan,Yuning Ma,Zhemin Shen
Oxidation is an attractive treatment method to effectively remove organic contaminants in water. In this study, degradation of 30 organic compounds in different oxidation systems was evaluated, including oxygen (O 2 ), hydrogen peroxide (H 2 O 2 ), ozone (O 3 ) and hydroxyl radical (HO ). First, a quantitative structure-activity relationship (QSAR) model for oxidation-reduction potentials (ORPs) of organics was developed and exhibited a good performance to predict ORP values of organics with evaluation indices of squared correlation coefficient ( R 2 ) = 0.866, internal validation ( q 2 ) = 0.811 and external validation ( Q e x t 2 ) = 0.669. Four quantum parameters, including f ( + ) n , f ( − ) n , E H O M O and E B 3 L Y P dominate the ORP values. Subsequently, a relationship between reaction rates ( k ) and the difference of ORP for oxidants and organics ( Δ E o x i − o r g ) was established, however, which was limited ( R 2 = 0.697). Therefore, two new predictors (slopes and intercepts) are proposed based on the linear relationships between k values and ORPs of oxidants. These new predictors can be applied to estimate the reaction rates and minimum oxidation potential for organic compounds. Afterwards, to express the two predictors, QSAR models were established. The two optimal QSAR models fitted very well with experimental values and were demonstrated to be stable and accurate based on R 2 (0.982 and 0.965), q 2 (0.950 and 0.950) and Q e x t 2 (0.985 and 0.989). B O x , q ( H ) + and q ( C ) x were main factors influencing the slopes and intercepts. This study developed methods to predict ORPs of organics and established two new predictors to estimate the reaction rates undergoing different oxidation processes, offering new insights into the oxidant selection.
研究领域:
环境科学
·
化学
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DOI
高影响因子
Molecular Informatics
·
2017
·Vol. 36
·期 9
·1600157
·
IF 1.955
Chunyan Qi,Guimei Lin,Rong Zhang,Wenjuan Wu
Graphical 3D-QSAR, molecular docking and activity evaluation were used to study the bioactivities of ACE-inhibitory peptides with phenylalanine C-terminus. Both CoMFA ( Q 2 =0.773, R 2 =0.992) and CoMSIA ( Q 2 =0.664, R 2 =0.990) models were constructed. According to the established models, four novel potent ACE-inhibitory tripeptides GEF, VEF, VRF, and VKF were synthesized. The IC 50 values were respectively determined to be 13 μM, 23 μM, 5 μM, and 11 μM by in vitro evaluation. The results show good agreement with the predicted values. The established models play an important role in revealing the structure-activity relationship of ACE-inhibitory peptides and designing novel peptides with enhanced biological activity.
研究领域:
药理学
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生物化学
·
计算化学
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产品关联
DOI
PubMed
高影响因子
FOOD AND CHEMICAL TOXICOLOGY
·
2023
·
IF 4.3
Sailing Chen,Shaowei Wang,Jingyi Zheng,Han Lu,Huiqian Chen,Yunbing Tang,Nan Wang,Yang Zhu,Yiyan Wang,Ping Duan,Ren-shan Ge
Bisphenols , estrogenic endocrine-disrupting chemicals, disrupt at least one of three endocrine pathways (estrogen, androgen, and thyroid). 17β-Hydroxysteroid dehydrogenase 1 (17β-HSD1) is a steroidogenic enzyme that catalyzes the activation of estradiol from estrone in human placenta and rat ovary. However, whether bisphenols inhibit 17β-HSD1 and the mode of action remains unclear. This study we screened 17 bisphenols for inhibiting human 17β-HSD1 in placental microsomes and rat 17β-HSD1 in ovarian microsomes and determined 3D-quantitative structure-activity relationship (3D-QSAR) and mode of action. We observed some bisphenols with substituents were found to significantly inhibit both human and rat 17β-HSD1 with the most potent inhibition on human enzyme by bisphenol H (IC 50 = 0.90 μM) when compared to bisphenol A (IC 50 = 113.38 μM). Rat enzyme was less sensitive to the inhibition of bisphenols than human enzyme with bisphenol H (IC 50 = 32.94 μM) for rat enzyme. We observed an inverse correlation between IC 50 and hydrophobicity (expressed as Log P). Docking analysis showed that they bound steroid-binding site of 17β-HSD1. The 3D-QSAR models demonstrated that hydrophobic region, hydrophobic aromatic, ring aromatic, and hydrogen bond acceptor are key factors for the inhibition of steroid synthesis activity of 17β-HSD1.
研究领域:
分子生物学
·
内分泌学
·
毒理学
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产品关联
DOI
PubMed
高影响因子
PROCESS BIOCHEMISTRY
·
2023
·
IF 4.4
Qi Liu,Shan Shao,Jingyu Bao,Syed Jalil Shah,Shumin Yue,Xinqi Luan,Qing Liu,Linguang Xing,Zhongfeng Shi,Zhenxia Zhao,Zhongxing Zhao
The 3D-QSAR model is one of the most effective techniques for predicting the peptide bioactivity based on their structure properties. The accuracy of model prediction is highly dependent on the bio-activity of the peptides in its dataset. However, the same peptide used for constructing the database was reported to have obviously different activities in different published articles, which may significantly decrease the prediction accuracy. Based on this, we chose ACE inhibitory (ACE-I) dipeptides that can be absorbed directly into the human small intestine as research object. Ten dipeptides were randomly selected from the literatures for molecular docking with ACE and synthesized to test their activity. Ultimately, a linear equation was developed between bio-activities and docking scores, which was used to revalidate the reliable ACE-I activities of all reported dipeptides for constructing a credible dataset of 3D-QSAR model. The prediction accuracy was significantly enhanced and the model we established had a high Q 2 = 0.840 and R 2 = 0.998. Furthermore, dipeptide CW was predicted and tested in vitro to achieve the highest ACE-I activity (IC 50 = 0.16 μM), and the inhibition mechanism was also investigated. This study introduced a new method for predicting bio-activity with high precision using the 3D-QSAR model.
研究领域:
生物信息学
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药物化学
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生物化学
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产品关联
DOI
高影响因子
PEST MANAGEMENT SCIENCE
·
2024
·
IF 3.8
Liangliang Cheng,Cong Zhou,Qinglong Yuan,Letian Zhang,Xusheng Shao,Xiaoyong Xu,Zhong Li,Jiagao Cheng
BACKGROUND Succinate dehydrogenase inhibitor (SDHI) fungicides play important roles in the control of plant fungal diseases. However, they are facing serious challenges from issues with resistance and cross-resistance, primarily attributed to their frequent application and structural similarities. There is an urgent need to design and develop SDHI fungicides with novel structures. RESULTS Aiming to discover novel potent SDHI fungicides, 31 innovative pyrazole β -ketonitrile derivatives with diphenyl ether moiety were rationally designed and synthesized, which were guided by a 3D-QSAR model from our previous study. The optimal target compound A23 exhibited not only outstanding in vitro inhibitory activities against Rhizoctonia solani with a half-maximal effective concentration (EC 50 ) value of 0.0398 μg mL −1 comparable to that for fluxapyroxad (EC 50 = 0.0375 μg mL −1 ), but also a moderate protective efficacy in vivo against rice sheath blight. Porcine succinate dehydrogenase (SDH) enzymatic inhibitory assay revealed that A23 is a potent inhibitor of SDH, with a half-maximal inhibitory concentration of 0.0425 μ m . Docking study within R. solani SDH indicated that A23 effectively binds into the ubiquinone site mainly through hydrogen-bonds, and cation–π and π–π interactions. CONCLUSION The identified β -ketonitrile compound A23 containing diphenyl ether moiety is a potent SDH inhibitor, which might be a good lead for novel fungicide research and optimization. © 2024 Society of Chemical Industry.
研究领域:
植物保护学
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药物化学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
FOOD RESEARCH INTERNATIONAL
·
2021
·
IF 6.475
Shan Shao,Huaju Sun,Yaseen Muhammad,Hong Huang,Ruimeng Wang,Shuangxi Nie,Meiyun Huang,Ziyi Zhao,Zhongxing Zhao
Efficient screening of angiotensin converting enzyme inhibitory (ACE-I) peptides from agricultural or edible sources attract increasing attention. However, their purification process from the complex natural system is still semi-empirical or even uncontrollable, which has seriously reduced their screening efficiency. Herein, inspired by the prediction of ACE-I activity, 3D-QSAR was proposed to predict the adsorption performance of peptides from sericin hydrolysate (SH) having high ACE-I activity on porous hypercross-linked polymers according to their molecular structures. Thiophene hypercross-linked polymer (T-HCP) possessing better screening capacity for ACE-I peptides was chosen as our research object in this work. The sequence and relative adsorption rate of 101 peptides in SH were analyzed by LC-MS and was used as a database to construct the relationship of peptide’s chemical structure and adsorption performance on T-HCP by Comparative molecular similarity indices analysis (CoMSIA) from 3D-QSAR. Optimum CoMSIA revealed that enhanced interaction of hydrophobicity and H-bond between T-HCP and the peptide was conducive to increase the adsorption performance of di- to hexa- peptides. Based on these relationships, the adsorption capability of 24 designed peptides with distinguished hydrophobic and H-bond fields was predicted on T-HCP by using optimum CoMSIA and the results of half of these were verified, which showed high consistency with their predicted adsorption rate. Interestingly, these peptides having higher adsorption capacities on T-HCP also possessed higher ACE-I activity. This can be attributed to the high concentration of aromatic surface with π-π interaction and weak-polar C S C group with H-bond interaction on T-HCP material, which is ideal for the selective adsorption of peptides with higher ACE-I activity from SH. This study provides important theoretical guidance for the industrial screening of bio-functional peptides from complex protein mixtures.
研究领域:
生物化学
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食品科学
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药物开发
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DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）