SAR and QSAR in Environmental Research最新文献_第3页

Computational investigations of flavonoids as ALDH isoform inhibitors for treatment of cancer. 黄酮类化合物作为 ALDH 同工酶抑制剂治疗癌症的计算研究。

IF 4.6 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-10-01 Epub Date: 2024-11-06 DOI: 10.1080/1062936X.2024.2415593

M A Mohamed, T Elsaman, M S Mohamed, E M Eltayib

{"title":"Computational investigations of flavonoids as ALDH isoform inhibitors for treatment of cancer.","authors":"M A Mohamed, T Elsaman, M S Mohamed, E M Eltayib","doi":"10.1080/1062936X.2024.2415593","DOIUrl":"10.1080/1062936X.2024.2415593","url":null,"abstract":"Human aldehyde dehydrogenases (ALDHs) are a group of 19 isoforms often overexpressed in cancer stem cells (CSCs). These enzymes play critical roles in CSC protection, maintenance, cancer progression, therapeutic resistance, and poor prognosis. Thus, targeting ALDH isoforms offers potential for innovative cancer treatments. Flavonoids, known for their ability to affect multiple cancer-related pathways, have shown anticancer activity by downregulating specific ALDH isoforms. This study aimed to evaluate 830 flavonoids from the PubChem database against five ALDH isoforms (ALDH1A1, ALDH1A2, ALDH1A3, ALDH2, ALDH3A1) using computational methods to identify potent inhibitors. Extra precision (XP) Glide docking and MM-GBSA free binding energy calculations identified several flavonoids with high binding affinities. MD simulation highlighted flavonoids 1, 2, 18, 27, and 42 as potential specific inhibitors for each isoform, respectively. Flavonoid 10 showed high binding affinities for ALDH1A2, ALDH1A3, and ALDH3A1, emerging as a potential multi-ALDH inhibitor. ADMET property evaluation indicated that the promising hits have acceptable drug-like profiles, but further optimization is needed to enhance their therapeutic efficacy and reduce toxicity, making them more effective ALDH inhibitors for future cancer treatment.","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":" ","pages":"837-875"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142584265","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Molecular mechanism underlying effect of D93 and D289 protonation states on inhibitor-BACE1 binding: exploration from multiple independent Gaussian accelerated molecular dynamics and deep learning. D93和D289质子化状态对抑制剂-BACE1结合影响的分子机制：从多个独立的高斯加速分子动力学和深度学习中探索。

IF 4.6 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-10-01 Epub Date: 2024-11-08 DOI: 10.1080/1062936X.2024.2419911

J Du, G Xu, W Zhang, J Cong, X Si, B Wei

{"title":"Molecular mechanism underlying effect of D93 and D289 protonation states on inhibitor-BACE1 binding: exploration from multiple independent Gaussian accelerated molecular dynamics and deep learning.","authors":"J Du, G Xu, W Zhang, J Cong, X Si, B Wei","doi":"10.1080/1062936X.2024.2419911","DOIUrl":"10.1080/1062936X.2024.2419911","url":null,"abstract":"BACE1 has been regarded as an essential drug design target for treating Alzheimer's disease (AD). Multiple independent Gaussian accelerated molecular dynamics simulations (GaMD), deep learning (DL), and molecular mechanics general Born surface area (MM-GBSA) method are integrated to elucidate the molecular mechanism underlying the effect of D93 and D289 protonation on binding of inhibitors OV6 and 4B2 to BACE1. The GaMD trajectory-based DL successfully identifies significant function domains. Dynamic analysis shows that the protonation of D93 and D289 strongly affects the structural flexibility and dynamic behaviour of BACE1. Free energy landscapes indicate that inhibitor-bound BACE1s have more conformational states in the protonated states than the wild-type (WT) BACE1, and show more binding poses of inhibitors. Binding affinities calculated using the MM-GBSA method indicate that the protonation of D93 and D289 highly disturbs the binding ability of inhibitors to BACE1. In addition, the protonation of two residues significantly affects the hydrogen bonding interactions (HBIs) of OV6 and 4B2 with BACE1, altering their binding activity to BACE1. The binding hot spots of BACE1 recognized by residue-based free energy estimations provide rational targeting sites for drug design towards BACE1. This study is anticipated to provide theoretical aids for drug development towards treatment of AD.","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":" ","pages":"919-947"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142606101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Exploiting the chemical diversity space of phosphopeptide binding to nasopharyngeal carcinoma PLK1 PBD domain with unnatural amino acid building blocks by using QSAR-based genetic optimization. 利用基于 QSAR 的遗传优化，探索非天然氨基酸构件的磷酸肽与鼻咽癌 PLK1 PBD 结构域结合的化学多样性空间。

IF 2.3 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-10-01 Epub Date: 2024-11-18 DOI: 10.1080/1062936X.2024.2418355

R Y Ma, J Yang, J J Wu, H Y Zhu

{"title":"Exploiting the chemical diversity space of phosphopeptide binding to nasopharyngeal carcinoma PLK1 PBD domain with unnatural amino acid building blocks by using QSAR-based genetic optimization.","authors":"R Y Ma, J Yang, J J Wu, H Y Zhu","doi":"10.1080/1062936X.2024.2418355","DOIUrl":"10.1080/1062936X.2024.2418355","url":null,"abstract":"Human polo-like kinase 1 (PLK1) has been recognized as an attractive therapeutic target against nasopharyngeal carcinoma (NPC). The kinase contains a conserved polo-box domain (PBD) that exhibits a wide specificity across various substrates. Previously, we explored natural amino acid preference in PLK1 PBD-binding phosphopeptides. However, limited to the short sequence only natural amino acids cannot guarantee the sufficient exploitation of chemical and structural diversity of the phosphopeptides. Here, we described a genetic optimization (GO) strategy to systematically optimize a 104-sized 6-mer phosphopeptide array towards increasing affinity to PLK1 PBD domain by using 20 natural plus 34 unnatural amino acids as basic building blocks. A QSAR predictor was created to guide the GO optimization and then evaluated rigorously at molecular and cellular levels. Three unnatural phosphopeptides uPP8, uPP15 and uPP20 were designed as potent binders with Kd = 0.18, 0.42 and 0.08 μM, respectively, in which the uPP20 also possessed a good anti-tumor activity against human NPC cells when fused with cell permeation sequence. In addition, we defined a relaxed 6-mer motif for the preferential PLK1 PBD-binding phosphosites, namely [Φ/П]-3-[ζ]-2-[ζ]-1-[pT/pS]0-[Φ/П]+1-[Φ]+2, where the symbols Φ, ζ and П represent hydrophobic, polar and aromatic amino acid types, respectively. .","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":"35 10","pages":"899-918"},"PeriodicalIF":2.3,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142648591","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Dithiocarbamate fungicides suppress aromatase activity in human and rat aromatase activity depending on structures: 3D-QSAR analysis and molecular simulation. 二硫代氨基甲酸盐杀菌剂抑制人和大鼠芳香化酶的活性取决于其结构：3D-QSAR 分析和分子模拟。

IF 4.6 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-10-01 Epub Date: 2024-10-30 DOI: 10.1080/1062936X.2024.2420243

Z Ji, H Chen, J I Zheng, J Yan, H Lu, J He, Y Zhu, S Wang, L Li, R S Ge, Y Liu

{"title":"Dithiocarbamate fungicides suppress aromatase activity in human and rat aromatase activity depending on structures: 3D-QSAR analysis and molecular simulation.","authors":"Z Ji, H Chen, J I Zheng, J Yan, H Lu, J He, Y Zhu, S Wang, L Li, R S Ge, Y Liu","doi":"10.1080/1062936X.2024.2420243","DOIUrl":"10.1080/1062936X.2024.2420243","url":null,"abstract":"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.","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":" ","pages":"949-970"},"PeriodicalIF":4.6,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547098","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Correction. 更正。

IF 2.3 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-10-01 Epub Date: 2024-11-18 DOI: 10.1080/1062936X.2024.2429238

引用次数: 0

Analysis of oral and inhalation toxicity of per- and polyfluoroalkylated organic compounds in rats and mice using multivariate QSAR. 利用多元 QSAR 分析全氟烷基化和多氟烷基化有机化合物对大鼠和小鼠的口服和吸入毒性。

IF 4.6 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-10-01 Epub Date: 2024-10-18 DOI: 10.1080/1062936X.2024.2417250

N A B R da Silva, E B de Melo

引用次数: 0

Exploring molecular fragments for fraction unbound in human plasma of chemicals: a fragment-based cheminformatics approach. 探索人体血浆中化学品未结合部分的分子片段：基于片段的化学信息学方法。

IF 2.3 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-09-01 Epub Date: 2024-10-18 DOI: 10.1080/1062936X.2024.2415602

S Banerjee, A Bhattacharya, I Dasgupta, S Gayen, S A Amin

{"title":"Exploring molecular fragments for fraction unbound in human plasma of chemicals: a fragment-based cheminformatics approach.","authors":"S Banerjee, A Bhattacharya, I Dasgupta, S Gayen, S A Amin","doi":"10.1080/1062936X.2024.2415602","DOIUrl":"https://doi.org/10.1080/1062936X.2024.2415602","url":null,"abstract":"Fraction unbound in plasma (fu,p) of drugs is an significant factor for drug delivery and other biological incidences related to the pharmacokinetic behaviours of drugs. Exploration of different molecular fragments for fu,p of different small molecules/agents can facilitate in identification of suitable candidates in the preliminary stage of drug discovery. Different researchers have implemented strategies to build several prediction models for fu,p of different drugs. However, these studies did not focus on the identification of responsible molecular fragments to determine the fraction unbound in plasma. In the current work, we tried to focus on the development of robust classification-based QSAR models and evaluated these models with multiple statistical metrics to identify essential molecular fragments/structural attributes for fractions unbound in plasma. The study unequivocally suggests various N-containing aromatic rings and aliphatic groups have positive influences and sulphur-containing thiadiazole rings have negative influences for the fu,p values. The molecular fragments may help for the assessment of the fu,p values of different small molecules/drugs in a speedy way in comparison to experiment-based in vivo and in vitro studies.","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":"35 9","pages":"817-836"},"PeriodicalIF":2.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142473744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

QSAR modelling of enzyme inhibition toxicity of ionic liquid based on chaotic spotted hyena optimization algorithm. 基于混沌斑鬣狗优化算法的离子液体酶抑制毒性 QSAR 模型。

IF 2.3 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-09-01 Epub Date: 2024-09-30 DOI: 10.1080/1062936X.2024.2404853

A M Alharthi, N A Al-Thanoon, A M Al-Fakih, Z Y Algamal

{"title":"QSAR modelling of enzyme inhibition toxicity of ionic liquid based on chaotic spotted hyena optimization algorithm.","authors":"A M Alharthi, N A Al-Thanoon, A M Al-Fakih, Z Y Algamal","doi":"10.1080/1062936X.2024.2404853","DOIUrl":"10.1080/1062936X.2024.2404853","url":null,"abstract":"Ionic liquids (ILs) have attracted considerable interest due to their unique properties and prospective uses in various industries. However, their potential toxicity, particularly regarding enzyme inhibition, has become a growing concern. In this study, a QSAR model was proposed to predict the enzyme inhibition toxicity of ILs. A dataset of diverse ILs with corresponding toxicity data against three enzymes was compiled. Molecular descriptors that capture the physicochemical, structural, and topological properties of the ILs were calculated. To optimize the selection of descriptors and develop a robust QSAR model, the chaotic spotted hyena optimization algorithm, a novel nature-inspired metaheuristic, was employed. The proposed algorithm efficiently searches for an optimal subset of descriptors and model parameters, enhancing the predictive performance and interpretability of the QSAR model. The developed model exhibits excellent predictive capability, with high classification accuracy and low computation time. Sensitivity analysis and molecular interpretation of the selected descriptors provide insights into the critical structural features influencing the toxicity of ILs. This study showcases the successful application of the chaotic spotted hyena optimization algorithm in QSAR modelling and contributes to a better understanding of the toxicity mechanisms of ILs, aiding in the design of safer alternatives for industrial applications.","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":" ","pages":"757-770"},"PeriodicalIF":2.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142353052","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Deciphering Cathepsin K inhibitors: a combined QSAR, docking and MD simulation based machine learning approaches for drug design. 解密 Cathepsin K 抑制剂：基于 QSAR、对接和 MD 模拟的机器学习药物设计组合方法。

IF 2.3 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-09-01 Epub Date: 2024-10-09 DOI: 10.1080/1062936X.2024.2405626

S Ilyas, J Lee, Y Hwang, Y Choi, D Lee

{"title":"Deciphering Cathepsin K inhibitors: a combined QSAR, docking and MD simulation based machine learning approaches for drug design.","authors":"S Ilyas, J Lee, Y Hwang, Y Choi, D Lee","doi":"10.1080/1062936X.2024.2405626","DOIUrl":"10.1080/1062936X.2024.2405626","url":null,"abstract":"Cathepsin K (CatK), a lysosomal cysteine protease, contributes to skeletal abnormalities, heart diseases, lung inflammation, and central nervous system and immune disorders. Currently, CatK inhibitors are associated with severe adverse effects, therefore limiting their clinical utility. This study focuses on exploring quantitative structure-activity relationships (QSAR) on a dataset of CatK inhibitors (1804) compiled from the ChEMBL database to predict the inhibitory activities. After data cleaning and pre-processing, a total of 1568 structures were selected for exploratory data analysis which revealed physicochemical properties, distributions and statistical significance between the two groups of inhibitors. PubChem fingerprinting with 11 different machine-learning classification models was computed. The comparative analysis showed the ET model performed well with accuracy values for the training set (0.999), cross-validation (0.970) and test set (0.977) in line with OECD guidelines. Moreover, to gain structural insights on the origin of CatK inhibition, 15 diverse molecules were selected for molecular docking. The CatK inhibitors (1 and 2) exhibited strong binding energies of -8.3 and -7.2 kcal/mol, respectively. MD simulation (300 ns) showed strong structural stability, flexibility and interactions in selected complexes. This synergy between QSAR, docking, MD simulation and machine learning models strengthen our evidence for developing novel and resilient CatK inhibitors.","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":" ","pages":"771-793"},"PeriodicalIF":2.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Discovery of novel chemotype inhibitors targeting Anaplastic Lymphoma Kinase receptor through ligand-based pharmacophore modelling. 通过基于配体的药理模型，发现针对淋巴瘤激酶受体的新型化学抑制剂。

IF 2.3 3区环境科学与生态学

SAR and QSAR in Environmental Research Pub Date : 2024-09-01 Epub Date: 2024-10-09 DOI: 10.1080/1062936X.2024.2406398

I El-Jundi, S Daoud, M O Taha

{"title":"Discovery of novel chemotype inhibitors targeting Anaplastic Lymphoma Kinase receptor through ligand-based pharmacophore modelling.","authors":"I El-Jundi, S Daoud, M O Taha","doi":"10.1080/1062936X.2024.2406398","DOIUrl":"10.1080/1062936X.2024.2406398","url":null,"abstract":"Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase within the insulin receptor superfamily. Alterations in ALK, such as rearrangements, mutations, or amplifications, have been detected in various tumours, including lymphoma, neuroblastoma, and non-small cell lung cancer. In this study, we outline a computational workflow designed to uncover new inhibitors of ALK. This process starts with a ligand-based exploration of the pharmacophoric space using 13 diverse sets of ALK inhibitors. Subsequently, quantitative structure-activity relationship (QSAR) modelling is employed in combination with a genetic function algorithm to identify the optimal combination of pharmacophores and molecular descriptors capable of elucidating variations in anti-ALK bioactivities within a compiled list of inhibitors. The successful QSAR model revealed three pharmacophores, two of which share three similar features, prompting their merger into a single pharmacophore model. The merged pharmacophore was used as a 3D search query to mine the National Cancer Institute (NCI) database for novel anti-ALK leads. Subsequent in vitro bioassay of the top 40 hits identified two compounds with low micromolar IC50 values. Remarkably, one of the identified leads possesses a novel chemotype compared to known ALK inhibitors.","PeriodicalId":21446,"journal":{"name":"SAR and QSAR in Environmental Research","volume":" ","pages":"795-815"},"PeriodicalIF":2.3,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142392952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"环境科学与生态学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0