Molecular Diversity最新文献_第3页

Design and synthesis of glycyrrhetinic acid glycosides against acute lung injury and pulmonary fibrosis.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-12-02 DOI: 10.1007/s11030-024-11058-6

Wei Li, Jianrong Liu, Tianbo Wu, Xin Qiang, Yijie Peng, Quanyi Zhao, Dian He

{"title":"Design and synthesis of glycyrrhetinic acid glycosides against acute lung injury and pulmonary fibrosis.","authors":"Wei Li, Jianrong Liu, Tianbo Wu, Xin Qiang, Yijie Peng, Quanyi Zhao, Dian He","doi":"10.1007/s11030-024-11058-6","DOIUrl":"https://doi.org/10.1007/s11030-024-11058-6","url":null,"abstract":"HMGB1 mediated signalling pathway plays an important role in acute injury and fibrosis in lung tissues. Glycyrrhizic acid (GL) is a HMGB1 inhibitor, and its aglycone (glycyrrhetinic acid, GA) is the major pharmacophore and plays the main role during binding to HMGB1. To improve selectivity for these lung diseases, a series of novel glycyrrhetinic acid glycosides targeting mannose acceptors in the respiratory tract and lung tissues were synthesised, and their biological activities were evaluated in vitro and in vivo. For normal lung cell lines WI-38 and Beas-2B, all the compounds but c6 showed reduced cytotoxicity vs the positive controls (GA and GL), IC50 values were > 800 µM. For three cancer cells, c1 exhibited high selectivity for lung cancer cells A549. In the inflammation assays, compound c1 displayed the strongest activity of NO inhibition, and c4 was next; both them not only down-regulated the expression levels of IL-1β and TNF-α in RAW264.7 cells, but also decreased the levels of TNF-α, IL-1β, HMGB1, RAGE and ROS in A549 cells in a dose-dependent manner. Noteworthy, compound c1 of 50 μM reduced the levels of HMGB1 and RAGE to 38.4 and 37.0% of the LPS group, and it showed much higher binding affinity with HMGB1 than GL, which confirmed by molecular docking; in addition, c1 also inhibited the deposition of α-SMA and Col-1 proteins in TGF-β1-activated A549 cells. In the bleomycin-induced lung fibrosis mouse model, c1 decreased fibrous protein production and deposition in the lung tissues; at a 30 mg/kg dose, it reduced the levels of α-SMA and Col-1 to 48.12 and 56.37% of the BLM group, respectively. The pharmacokinetics tests showed c1 relative distribution rate in lung tissue (at 1 h, 18.86%; at 2 h, 12.80%) is much higher than that of GA (at 1 h, 2.8%; at 2 h, 1.9%). These results show compound c1 is likely to be a candidate for acute lung injury and pulmonary fibrosis.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Chalcone derivatives containing 1,2,4-triazole and pyridine moiety: design, synthesis, and antiviral activity.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-12-02 DOI: 10.1007/s11030-024-11049-7

Hui Xin, Jiao Tian, Tianyu Deng, Qing Zhou, Yuhong Wang, Hong Fu, Haotao Pu, Wei Xue

引用次数: 0

New frontiers in multicomponent mechanosynthesis for organic molecules: modern marvels.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-12-01 DOI: 10.1007/s11030-024-11053-x

Hiren R Chaudhary, Divyang M Patel

{"title":"New frontiers in multicomponent mechanosynthesis for organic molecules: modern marvels.","authors":"Hiren R Chaudhary, Divyang M Patel","doi":"10.1007/s11030-024-11053-x","DOIUrl":"https://doi.org/10.1007/s11030-024-11053-x","url":null,"abstract":"In the past, mechanochemical approaches in organic synthesis were largely overlooked, but their perception within the synthetic community has shifted in recent years, marking a trend toward becoming mainstream. Mechanochemical multicomponent organic synthesis has garnered significant interest from both the academic and industrial chemical sectors. The efficiency and environmental friendliness of procedures conducted through mechanical activation have established mechanical procedures as prominent green techniques. Notably, utilizing solid starting materials under mechanochemical conditions empowers the development of novel multicomponent reactions that are often unfeasible in traditional solution-based processes. This capability not only enhances the diversity of accessible organic compounds but also sparks new avenues for innovative synthetic strategies. This approach facilitates the effective fulfillment of sustainable chemistry goals. In this context, we emphasize the major progress and advancements in mechanochemical multicomponent reactions from 2017 to 2024. This article covers the foremost multicomponent mechanosynthesis for developing organic molecules through carbon-carbon and carbon-heteroatom coupling reactions and multicomponent mechanosynthesis for monocyclic and fused heterocycles.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A multitask interpretable model with graph attention mechanism for activity prediction of low-data PIM inhibitors.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-11-30 DOI: 10.1007/s11030-024-11060-y

Zixiao Wang, Lili Sun, Yu Chang, Fang Yang, Kai Jiang

{"title":"A multitask interpretable model with graph attention mechanism for activity prediction of low-data PIM inhibitors.","authors":"Zixiao Wang, Lili Sun, Yu Chang, Fang Yang, Kai Jiang","doi":"10.1007/s11030-024-11060-y","DOIUrl":"https://doi.org/10.1007/s11030-024-11060-y","url":null,"abstract":"The aberrant expression of proviral integration site for Moloney murine leukemia virus (PIM) kinases is closely related to various tumors and chemotherapy resistance, making them attractive targets for cancer therapy. However, due to the extremely high homology among the three PIM isoforms (PIM1, PIM2, PIM3) and the limited availability of existing bioactivity data, screening and designing selective PIM inhibitors remain a daunting challenge. To address this issue, this study constructed a multitask regression model that can simultaneously predict the half-maximal inhibitory concentration (IC50 values). The model utilizes an attention mechanism to capture effects within local atomic groups and the interactions between different groups of atoms. Through weight sharing, the model enhances the accuracy of predicting PIM3 inhibitors by leveraging the rich and highly correlated data from PIM1 and PIM2 isoforms. Additionally, visualizing the weights of nodes (atoms in the molecule) in the model helps us to intuitively understand the relationship between molecular features and prediction outcomes, thereby enhancing the interpretability of the model. In summary, this work provides new insights and methods for performing activity prediction tasks for multiple similar targets in low-data scenarios.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142765266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Generative adversarial network (GAN) model-based design of potent SARS-CoV-2 M^pro inhibitors using the electron density of ligands and 3D binding pockets: insights from molecular docking, dynamics simulation, and MM-GBSA analysis.

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-11-30 DOI: 10.1007/s11030-024-11047-9

Annesha Chakraborty, Vignesh Krishnan, Subbiah Thamotharan

{"title":"Generative adversarial network (GAN) model-based design of potent SARS-CoV-2 Mpro inhibitors using the electron density of ligands and 3D binding pockets: insights from molecular docking, dynamics simulation, and MM-GBSA analysis.","authors":"Annesha Chakraborty, Vignesh Krishnan, Subbiah Thamotharan","doi":"10.1007/s11030-024-11047-9","DOIUrl":"https://doi.org/10.1007/s11030-024-11047-9","url":null,"abstract":"Deep learning-based generative adversarial network (GAN) frameworks have recently been developed to expedite the drug discovery process. These models generate novel molecules from scratch and validate them through molecular docking simulation to identify the most promising candidates for a given drug target. In this study, the SARS-CoV-2 main protease (Mpro) was selected as the drug target. Two distinct GAN algorithms were employed to generate novel small molecules. One approach utilized experimental electron density (ED-based) data of ligands for training to generate drug-like molecules, while the second approach leveraged the target binding pocket to capture spatial and bonding relationship between atoms within the binding pockets. The ED-based approach generated approximately 26,000 molecules, whereas the binding pocket-based method produced around 100 molecules. These generated molecules were subsequently ranked based on molecular docking results using the glide XP score (both flexible and rigid docking) and AutoDock Vina. To identify the most potent GAN-derived molecules, molecular docking was also performed on co-crystallized inhibitor molecules of Mpro. The six most promising molecules from these GAN approaches were further evaluated for stability, interactions, and MM-GBSA binding free energy through molecular dynamics simulations. This analysis led to the identification of four potent Mpro inhibitor molecules, all featuring a 2-benzyl-6-bromophenol scaffold. The binding free energies of these compounds were compared with those of other Mpro inhibitors, revealing that our compounds demonstrated better affinity for Mpro than some broad-spectrum protease inhibitors. The dynamic cross-correlation matrix plot indicated strongly correlated and anti-correlated regions, potentially linked to ligand binding.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142754447","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Biophysical characterization and in silico analysis of natural and synthetic compounds targeting Listeria monocytogenes HtrA protease. 针对单核细胞增生李斯特菌 HtrA 蛋白酶的天然和合成化合物的生物物理特征和硅学分析。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-11-28 DOI: 10.1007/s11030-024-11050-0

M C Amrutha, Silja Wessler, Karthe Ponnuraj

{"title":"Biophysical characterization and in silico analysis of natural and synthetic compounds targeting Listeria monocytogenes HtrA protease.","authors":"M C Amrutha, Silja Wessler, Karthe Ponnuraj","doi":"10.1007/s11030-024-11050-0","DOIUrl":"https://doi.org/10.1007/s11030-024-11050-0","url":null,"abstract":"HtrA protein is a member of a serine protease family with dual functions as a protease and molecular chaperone. It is a virulence factor in many bacteria, including the food-borne pathogen Listeria monocytogenes (Lm), which induces listeriosis in humans. Hence, inhibitors of LmHtrA protease have great importance in the control of infection. Many natural compounds have been used in the inhibition studies of proteases; here, we have performed the inhibition studies of LmHtrA with 31 compounds from different origins. The spectrophotometric assays revealed that plant compounds are promising inhibitors of LmHtrA protease activity compared to other tested peptides and synthetic compounds. The green tea catechin, EGCG has been identified as an inhibitor of protease activity of LmHtrA with a low IC50 value of 0.754 ± 0.2 μM. The substrate cleavage analysis by SDS-PAGE and SPR experiments corroborates the spectrophotometric results by exhibiting protease inhibition and showing the micromolar affinity of EGCG with LmHtrA, respectively. The interaction between rLmHtrA and EGCG was investigated by fluorescence spectroscopy. The binding constant and the number of binding sites were determined as 1.86 × 10(5) M(-1) and 1.2, respectively. The molecular docking and dynamics results of LmHtrA-inhibitor complexes have provided new insights into the inhibition mechanism of LmHtrA compared with other serine proteases. The findings of this study may open up new avenues for the development of natural compound-based derivatives of LmHtrA inhibitors that might be more potent and less harmful to humans.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142737919","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In silico screening of phytochemicals against chromatin modifier, SETD7 for remodeling of the immunosuppressive tumor microenvironment in renal cancer. 针对染色质修饰因子 SETD7 重塑肾癌免疫抑制性肿瘤微环境的植物化学物质的硅学筛选。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-11-27 DOI: 10.1007/s11030-024-11038-w

Nikhil Gadewal, Diya Patidar, Abhiram Natu, Sanjay Gupta, Virupaksha Bastikar

{"title":"In silico screening of phytochemicals against chromatin modifier, SETD7 for remodeling of the immunosuppressive tumor microenvironment in renal cancer.","authors":"Nikhil Gadewal, Diya Patidar, Abhiram Natu, Sanjay Gupta, Virupaksha Bastikar","doi":"10.1007/s11030-024-11038-w","DOIUrl":"https://doi.org/10.1007/s11030-024-11038-w","url":null,"abstract":"The tumor microenvironment and immune evasion function in a complex cellular network profoundly challenge the clinical outcome of promising therapies. Our recently published study reported that the subset of genes upregulated in ccRCC due to H3K4me1 and DNA demethylation potentially leads to an immunosuppressive environment. Thus, modulating H3K4me1 chromatin modifier SETD7 with a natural inhibitor in combination with immunotherapy might improve the immune landscape for a better therapeutic outcome. The present study was conducted via virtual screening and MD simulation using compounds from the literature, IMPPAT, and SuperNatural database. The phytochemical IMPHY002979 showed better binding affinity and lower energy than the reported R-PFI-2 and cyproheptadine inhibitors. The phytochemicals interact with the SET domain through H-bonding, as confirmed by MD simulation and molecular interaction analysis. Further, the compound was assessed using ADME parameters and free energy estimation, showing better pharmacokinetic properties. Therefore, the non-accessibility of the histone methyltransferase activity domain of SET7 with IMPHY002979 can downregulate H3K4me1 and, thereby, the expression of genes potentially responsible for immunosuppressive TME. Thus, patient stratification based on molecular markers for immunotherapy and combining epigenetic modulators with therapeutic drugs will improve the efficacy of immunotherapy in ccRCC.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An overview on pharmaceutical applications of phosphodiesterase enzyme 5 (PDE5) inhibitors. 磷酸二酯酶 5 (PDE5) 抑制剂的制药应用概述。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-11-27 DOI: 10.1007/s11030-024-11016-2

Mohamed T M Nemr, Mostafa A Abdelaziz, Mohamed Teleb, Ahmed E Elmasry, Yaseen A A M Elshaier

{"title":"An overview on pharmaceutical applications of phosphodiesterase enzyme 5 (PDE5) inhibitors.","authors":"Mohamed T M Nemr, Mostafa A Abdelaziz, Mohamed Teleb, Ahmed E Elmasry, Yaseen A A M Elshaier","doi":"10.1007/s11030-024-11016-2","DOIUrl":"https://doi.org/10.1007/s11030-024-11016-2","url":null,"abstract":"Phosphodiesterase enzyme 5 (PDE5) inhibitors have emerged as one of the leading molecules for the treatment of erectile dysfunction (ED). PDE5 inhibitors are categorized structurally into several classes. PDE5 inhibitors have been a multidisciplinary endeavor that attracts the attention of researchers because of their multiple pharmaceutical applications. Beyond their action on ED, PDE5 inhibitors are widely used in treatment of benign prostatic hypertrophy (BPH), Eisenmenger's syndrome, Raynaud's Disease, Intrauterine growth retardation (IUGR), Mountain sickness, Bladder pain syndrome/interstitial cystitis (BPS/IC), pulmonary arterial hypertension and type II diabetes (insulin resistance). In addition, PDE5 inhibitors also show promising antiproliferative activity, anti-Alzheimer and COX-1/COX-2 inhibitory activity (anti-inflammatory). Pharmacokinetics, Pharmacogenetics and toxicity of PDE5 inhibitors were finally explored. The diverse therapeutic applications, the high feasibility of structural modification and the appropriate pharmacokinetic properties of PDE5 inhibitors have motivated researchers to develop new scaffolds that have been either under clinical trials or approved by FDA and utilize them to overcome some recent global concerns, such as COVID-19.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142724595","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Room temperature natural light promoted DMSO/O₂-catalyzed N-acylation reaction of imidazoles/triazoles with cyclopropenones. 室温自然光促进了咪唑/三唑与环丙烯酮的 DMSO/O2 催化 N-酰化反应。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-11-25 DOI: 10.1007/s11030-024-11039-9

Guo-Dong Shen, Zhi-Rong Zhao, Kun Bi, Yi Man, Jun-Tong Liu, Xian-Qiang Huang, Xin Lv

引用次数: 0

Synthesis of novel estradiol bisselenocyanate with unique 2-selenocyano-17-selenocyanoesteryl structure and evaluation of antitumor activity. 具有独特的 2-硒氰基-17-硒氰基teryl 结构的新型雌二醇双硒氰酸酯的合成及抗肿瘤活性评估。

IF 3.9 2区化学

Molecular Diversity Pub Date : 2024-11-24 DOI: 10.1007/s11030-024-11040-2

Tao Gan, Yang Cheng, Wenhao Tian, Zhiping Liu, Chunfang Gan, Yanmin Huang, Chunrui Cai, Jianguo Cui

{"title":"Synthesis of novel estradiol bisselenocyanate with unique 2-selenocyano-17-selenocyanoesteryl structure and evaluation of antitumor activity.","authors":"Tao Gan, Yang Cheng, Wenhao Tian, Zhiping Liu, Chunfang Gan, Yanmin Huang, Chunrui Cai, Jianguo Cui","doi":"10.1007/s11030-024-11040-2","DOIUrl":"https://doi.org/10.1007/s11030-024-11040-2","url":null,"abstract":"Cancer is one of the most significant diseases that afflict human beings. The pursuit of high efficacy and low-toxicity anticancer drugs has always been a paramount research objective for scientists. In the present study, we incorporated two selenocyano pharmacophores into the 2-site and 17-branch chain of the steroid nucleus in various manners, utilizing estradiol as the fundamental framework. Consequently, several estradiol bisselenocyanate compounds with a 2-selenocyano-17-selenocyanoester structure were synthesized. When compared to the positive control steroidal anti-tumor drug 2-methoxyestradiol, certain derivatives exhibited superior inhibitory activity against tumor cells in vitro, surpassing their monoselenocyanate precursors. The representative compound 4b induced programmed apoptosis in HeLa cells in a concentration-dependent manner during apoptosis and cell cycle experiments, while causing G2 phase arrest predominantly in the cell cycle. Moreover, compound 4b exhibited significant inhibitory effects on cell migration and demonstrated remarkable inhibitory activity against HeLa xenograft tumors in zebrafish models. These findings suggest that these compounds hold potential as promising candidates for anti-tumor drugs and warrant further investigation.","PeriodicalId":708,"journal":{"name":"Molecular Diversity","volume":" ","pages":""},"PeriodicalIF":3.9,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708675","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0