Pub Date : 2023-07-31DOI: 10.2174/1570180820666230731144315
C. Fourie, J. Bezuidenhout, A. Petzer, J. Petzer, Theunis T. Cloete
Novel antibiotics are needed to stem the rise of antimicrobial resistance. N-Methyl-2-phenylmaleimide (NMP) compounds previously synthesised by our research group are structural analogues of 2,3,5-substituted perhydropyrrolo[3,4-d]isoxazole-4,6-diones found by others to have antibacterial activity. This study aims to explain the significance of NMPs and their antibacterial activity. The antibacterial activity of the NMPs was determined against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. The partition coefficient of the NMPs and a pharmacophore model were used to explain their antibacterial activity. The Kirby Bauer Disc diffusion method was used to screen the NMPs for activity, while the broth microdilution method was used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the active NMPs. Using the in vitro antibacterial activity of 2,3,5-substituted perhydropyrrolo[3,4-d]isoxazole-4,6-diones, a common feature pharmacophore model was constructed and validated. The rank score, fit value, enrichment factor (EF20%), and receiver operating characteristic area under the curve (ROC-AUC) were used as validation metrics. The NMPs were only active against S. aureus, with compound 3 (4 µg/ml) being the most active. The majority of NMPs were bacteriostatic. A common feature pharmacophore model was validated (rank score: 120.5; fit value: 4; EF20%: 4.3; ROC-AUC: 0.9 ± 0.03) and showed that three hydrogen bond acceptors and a ring aromatic region are important for activity. Comparing the partition coefficient of the NMPs to their MIC a statistically significant correlation was found. NMPs can be used as lead compounds in future studies. The validated pharmacophore model and partition coefficient can be used to develop more active compounds.
{"title":"In vitro and in silico antibacterial evaluation of N-Methyl-2-phenylmaleimides","authors":"C. Fourie, J. Bezuidenhout, A. Petzer, J. Petzer, Theunis T. Cloete","doi":"10.2174/1570180820666230731144315","DOIUrl":"https://doi.org/10.2174/1570180820666230731144315","url":null,"abstract":"\u0000\u0000Novel antibiotics are needed to stem the rise of antimicrobial resistance. N-Methyl-2-phenylmaleimide (NMP) compounds previously synthesised by our research group are structural analogues of 2,3,5-substituted perhydropyrrolo[3,4-d]isoxazole-4,6-diones found by others to have antibacterial activity.\u0000\u0000\u0000\u0000This study aims to explain the significance of NMPs and their antibacterial activity. The antibacterial activity of the NMPs was determined against Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa. The partition coefficient of the NMPs and a pharmacophore model were used to explain their antibacterial activity.\u0000\u0000\u0000\u0000The Kirby Bauer Disc diffusion method was used to screen the NMPs for activity, while the broth microdilution method was used to determine the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of the active NMPs. Using the in vitro antibacterial activity of 2,3,5-substituted perhydropyrrolo[3,4-d]isoxazole-4,6-diones, a common feature pharmacophore model was constructed and validated. The rank score, fit value, enrichment factor (EF20%), and receiver operating characteristic area under the curve (ROC-AUC) were used as validation metrics.\u0000\u0000\u0000\u0000The NMPs were only active against S. aureus, with compound 3 (4 µg/ml) being the most active. The majority of NMPs were bacteriostatic. A common feature pharmacophore model was validated (rank score: 120.5; fit value: 4; EF20%: 4.3; ROC-AUC: 0.9 ± 0.03) and showed that three hydrogen bond acceptors and a ring aromatic region are important for activity. Comparing the partition coefficient of the NMPs to their MIC a statistically significant correlation was found.\u0000\u0000\u0000\u0000NMPs can be used as lead compounds in future studies. The validated pharmacophore model and partition coefficient can be used to develop more active compounds.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80918522","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-26DOI: 10.2174/1570180820666230726164112
Marilisa Pia Dimmito, L. Marinelli, I. Cacciatore, Anna Lucia Valeri, Alessandra Rapino, A. Stefano
Supramolecular self-assembly (SA) is a naturally occurring and free energy-driven process of molecules to produce nanostructured systems depending on the assembling environment. SA molecules have captivated the research attention since they possess singular physicochemical properties that are potentially useful to make the nanostructures quite suitable for biomedical applications, such as diagnostics, drug delivery, tissue engineering, and regenerative medicine. Due to their high biological activity and low toxicity, the self-assembly properties of peptides bid certain advantages as drugs and drug delivery platforms. Among the discovered self-assembling bioactive peptides (SAPs), antimicrobial peptides (AMPs) are widely distributed through plant and animal kingdoms and play a key role as an alternative strategy to fight infections bypassing conventional antimicrobial drugs, susceptible to antimicrobial resistance. Based on this evidence, in this review, we summarized the mechanism of the self-assembling of peptides, the main forces responsible for the SAPs formation, and the studies regarding their possible implication in infectious diseases as well as wound dressing materials.
{"title":"Self-assembling Peptides (SAPs) as Powerful Tools for the Preparation of Antimicrobial and Wound-healing Nanostructures","authors":"Marilisa Pia Dimmito, L. Marinelli, I. Cacciatore, Anna Lucia Valeri, Alessandra Rapino, A. Stefano","doi":"10.2174/1570180820666230726164112","DOIUrl":"https://doi.org/10.2174/1570180820666230726164112","url":null,"abstract":"\u0000\u0000Supramolecular self-assembly (SA) is a naturally occurring and free energy-driven process of molecules to produce nanostructured systems depending on the assembling environment. SA molecules have captivated the research attention since they possess singular physicochemical properties that are potentially useful to make the nanostructures quite suitable for biomedical applications, such as diagnostics, drug delivery, tissue engineering, and regenerative medicine. Due to their high biological activity and low toxicity, the self-assembly properties of peptides bid certain advantages as drugs and drug delivery platforms. Among the discovered self-assembling bioactive peptides (SAPs), antimicrobial peptides (AMPs) are widely distributed through plant and animal kingdoms and play a key role as an alternative strategy to fight infections bypassing conventional antimicrobial drugs, susceptible to antimicrobial resistance. Based on this evidence, in this review, we summarized the mechanism of the self-assembling of peptides, the main forces responsible for the SAPs formation, and the studies regarding their possible implication in infectious diseases as well as wound dressing materials.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81164187","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-26DOI: 10.2174/1570180820666230726160348
M. Onysko, D. Kut, M. Kut, O. Komarovska-Porokhnyavets, M. Kurka, V. Lubenets
The investigation is devoted to the assessment of the potential antimicrobial use of new chalcogen-functionalized thiazolo[2,3-b]quinazolin-5-ones, halides and trihalides of thiazolo[3,2-a]quinazolin-10-ium and tribromides thiazino[3,2-a]quinazolin-11-ium. The compounds under study were obtained by electrophilic intramolecular heterocyclization. A high bactericidal and fungicidal effect against some gram-positive and gram-negative bacteria and fungi has been revealed for the investigated compounds. The "structure-activity" relationship has been established; the influence of the chalcogen's nature and the type of substituents in the thiazoline and pyrimidine cycles on the biological activity of the investigated thiazolo- and thiazinoquinazolines is shown. Angular 4-methyl-5-oxo-1-((trihalogenotellanyl)methylidene)-8-(trifluoromethyl)-1,2,4,5-tetrahydrothiazolo[3,2-a]quinazolin-10-ium halides have been found to show the highest bactericidal activity to the gram-negative culture of Escherichia coli.
{"title":"Antimicrobial activity of halogen- and chalcogen-functionalized thiazoloquinazolines","authors":"M. Onysko, D. Kut, M. Kut, O. Komarovska-Porokhnyavets, M. Kurka, V. Lubenets","doi":"10.2174/1570180820666230726160348","DOIUrl":"https://doi.org/10.2174/1570180820666230726160348","url":null,"abstract":"\u0000\u0000The investigation is devoted to the assessment of the potential antimicrobial use of new chalcogen-functionalized thiazolo[2,3-b]quinazolin-5-ones, halides and trihalides of thiazolo[3,2-a]quinazolin-10-ium and tribromides thiazino[3,2-a]quinazolin-11-ium. The compounds under study were obtained by electrophilic intramolecular heterocyclization. A high bactericidal and fungicidal effect against some gram-positive and gram-negative bacteria and fungi has been revealed for the investigated compounds. The \"structure-activity\" relationship has been established; the influence of the chalcogen's nature and the type of substituents in the thiazoline and pyrimidine cycles on the biological activity of the investigated thiazolo- and thiazinoquinazolines is shown. Angular 4-methyl-5-oxo-1-((trihalogenotellanyl)methylidene)-8-(trifluoromethyl)-1,2,4,5-tetrahydrothiazolo[3,2-a]quinazolin-10-ium halides have been found to show the highest bactericidal activity to the gram-negative culture of Escherichia coli.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83449292","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-26DOI: 10.2174/1570180820666230726111321
Hamada Haba, H. Ghanem, O. Khaoua, A. Ouahab, N. Benbellat
The lead compounds isolated from medicinal plants constitute a matrix for research and discovery of new drugs using in silico study and molecular docking. This work explores the in silico study and the molecular docking of two rare phytochemicals, namely Microphynolide A (1) and Microphynolide B (2), isolated from the Saharan medicinal plant Thymelaea microphylla (Thymelaeaceae family). In the current work, several integrated web-based in silico pharmacokinetic tools were used to estimate the druggability of two isolated phytochemicals. In addition, molecular docking was conducted using AutoDockVina 4.2 to study the binding interactions with the targets predicted employing the PharmMapper server. The toxicological study was evaluated using ProTox-II online server. DFT methods were utilized to evaluate some physicochemical properties of structures, vibrational wavenumbers, and molecular electrostatic potentials. Molecules (1) and (2) showed good ADMET profiles and antineoplastic activity. Also, they exhibited non-toxicity and belong to the Toxicity class VI (LD50 >8000 mg/kg) with immunotoxic activity. A good correlation was observed between the experimental and theoretical IR spectra, with no negative values in the theoretical spectra indicating the high stability of these compounds. Docking simulation studies against protein receptors Sulfotransferase 1A1 (PDB ID: 1LS6) and Angiogenin (PDB ID: 1B1I) displayed good binding affinity values of -5.8 and -6.8 kcal/mol, respectively, with number of H-bonding interactions. Furthermore, the control molecules p-Nitrophenol (pNP), Dopamine, Axitinib and Bevacizumab displayed values of binding energies of -6.7, -6.7, -6.9 and -6.3 Kcal/mol, respectively. This study provides evidence supporting that the two molecules could be effective drugs to inhibit cancer cells and did not show any acute toxicity or mutagenic effects.
{"title":"In Silico Pharmacodynamics, Antineoplastic Activity and Molecular Docking of two Phytochemicals Isolated from Thymelaea microphylla","authors":"Hamada Haba, H. Ghanem, O. Khaoua, A. Ouahab, N. Benbellat","doi":"10.2174/1570180820666230726111321","DOIUrl":"https://doi.org/10.2174/1570180820666230726111321","url":null,"abstract":"\u0000\u0000The lead compounds isolated from medicinal plants constitute a matrix for research and discovery of new drugs using in silico study and molecular docking.\u0000\u0000\u0000\u0000This work explores the in silico study and the molecular docking of two rare phytochemicals, namely Microphynolide A (1) and Microphynolide B (2), isolated from the Saharan medicinal plant Thymelaea microphylla (Thymelaeaceae family).\u0000\u0000\u0000\u0000In the current work, several integrated web-based in silico pharmacokinetic tools were used to estimate the druggability of two isolated phytochemicals. In addition, molecular docking was conducted using AutoDockVina 4.2 to study the binding interactions with the targets predicted employing the PharmMapper server. The toxicological study was evaluated using ProTox-II online server. DFT methods were utilized to evaluate some physicochemical properties of structures, vibrational wavenumbers, and molecular electrostatic potentials.\u0000\u0000\u0000\u0000Molecules (1) and (2) showed good ADMET profiles and antineoplastic activity. Also, they exhibited non-toxicity and belong to the Toxicity class VI (LD50 >8000 mg/kg) with immunotoxic activity. A good correlation was observed between the experimental and theoretical IR spectra, with no negative values in the theoretical spectra indicating the high stability of these compounds. Docking simulation studies against protein receptors Sulfotransferase 1A1 (PDB ID: 1LS6) and Angiogenin (PDB ID: 1B1I) displayed good binding affinity values of -5.8 and -6.8 kcal/mol, respectively, with number of H-bonding interactions. Furthermore, the control molecules p-Nitrophenol (pNP), Dopamine, Axitinib and Bevacizumab displayed values of binding energies of -6.7, -6.7, -6.9 and -6.3 Kcal/mol, respectively.\u0000\u0000\u0000\u0000This study provides evidence supporting that the two molecules could be effective drugs to inhibit cancer cells and did not show any acute toxicity or mutagenic effects.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90323275","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-25DOI: 10.2174/1570180820666230725110021
Theunis T. Cloete, Alize Hoepfner, J. Bezuidenhout, A. Petzer, J. Petzer
Methylene blue and some of its analogues have known antibacterial activity, however their exact mechanism of action is unknown In this study, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of several methylene blue analogues were determined against five bacterial strains, whereafter the data were used to create and validate a pharmacophore model. The agar dilution method was used to screen the analogues for antibacterial activity, while the broth microdilution method was used to determine their MIC and MBC. A pharmacophore model was constructed and validated using the rank score, fit value, enrichment factor (EF10%), hit rate (HR10%) and receiver operating characteristic area under the curve (ROC-AUC) as metrics. Against Staphylococcus aureus, pyronin B (0.125 µg/ml) was more active than tetracycline (1 µg/ml) and pyronin Y (0.5 µg/ml), 1,9-dimethylmethylene blue (2 µg/ml), basic blue 3 (2 µg/ml), new methylene blue (2 µg/ml) and Nile blue (2 µg/ml) had similar activity compared to tetracycline. Pyronin B, 1,9-dimethylmethylene blue and new methylene blue were bactericidal. A pharmacophore model was created (rank score: 36.55, max. fit value: 3), which was able to identify active analogues out of the test set (EF10%: 2.83, HR10%: 28.57%, ROC-AUC: 0.84 ± 0.04). The pharmacophore model highlighted that a positive ionisable, aromatic ring as well as a hydrophobic moiety are important for antibacterial activity. Methylene blue analogues were found to have potent antibacterial activity and a pharmacophore model was created to understand the structural requirements for activity.
{"title":"In vitro Antibacterial Activity of Dye Compounds","authors":"Theunis T. Cloete, Alize Hoepfner, J. Bezuidenhout, A. Petzer, J. Petzer","doi":"10.2174/1570180820666230725110021","DOIUrl":"https://doi.org/10.2174/1570180820666230725110021","url":null,"abstract":"\u0000\u0000Methylene blue and some of its analogues have known antibacterial activity,\u0000however their exact mechanism of action is unknown\u0000\u0000\u0000\u0000In this study, the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) of several methylene blue analogues were determined against five bacterial strains, whereafter the data were used to create and validate a pharmacophore model.\u0000\u0000\u0000\u0000The agar dilution method was used to screen the analogues for antibacterial activity, while the\u0000broth microdilution method was used to determine their MIC and MBC. A pharmacophore model was\u0000constructed and validated using the rank score, fit value, enrichment factor (EF10%), hit rate (HR10%) and\u0000receiver operating characteristic area under the curve (ROC-AUC) as metrics.\u0000\u0000\u0000\u0000Against Staphylococcus aureus, pyronin B (0.125 µg/ml) was more active than tetracycline (1\u0000µg/ml) and pyronin Y (0.5 µg/ml), 1,9-dimethylmethylene blue (2 µg/ml), basic blue 3 (2 µg/ml), new\u0000methylene blue (2 µg/ml) and Nile blue (2 µg/ml) had similar activity compared to tetracycline. Pyronin\u0000B, 1,9-dimethylmethylene blue and new methylene blue were bactericidal. A pharmacophore model was\u0000created (rank score: 36.55, max. fit value: 3), which was able to identify active analogues out of the test\u0000set (EF10%: 2.83, HR10%: 28.57%, ROC-AUC: 0.84 ± 0.04). The pharmacophore model highlighted that a\u0000positive ionisable, aromatic ring as well as a hydrophobic moiety are important for antibacterial activity.\u0000\u0000\u0000\u0000Methylene blue analogues were found to have potent antibacterial activity and a pharmacophore model was created to understand the structural requirements for activity.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87654711","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-19DOI: 10.2174/1570180820666230719121525
M. Farzaei, Seyedsomaye Jasemi, Hosna Khazaei, S. Fakhri, Z. Samimi, I. Aneva
Lung cancer is a progressive disease with the highest incidence and mortality rate of other cancer types. Besides, the low efficacy of current treatments used against lung cancer urges the need for novel alternative treatments. Accordingly, quercetin (a flavonoid) has shown a mechanistic-based potential in preventing the progression of lung cancer. So, this study was designed to systematically review quercetin's therapeutic effects on the improvement of lung cancer. For this purpose, PubMed, Scopus and Cochrane library databases were searched based on the keywords lung cancer, lung carcinoma, lung adenocarcinoma and quercetin from 1997 to November 2021. We removed Non-English, repetitive, review and irrelevant articles according to title and abstract in the first step. After that, full-text screening was used to include the final studies. From a total of 4341 results, finally 36 articles were included in the study, which the whole confirmed the therapeutic effects of quercetin on the improvement of lung malignancy. They also proved that quercetin has a synergic effect with chemical drugs used for lung cancer treatment. From the mechanical point of view, quercetin has employed several signaling mediators for lung therapeutic applications. This systematic review summarizes the modulatory effects of quercetin on several dysregulated pathways, including growth/proliferation, viability, migration/invasion, oxidative stress, inflammation and apoptosis. Prevailing studies show that quercetin interferes with molecular targets and mechanisms underlying lung cancer to prevent the development of such diseases in clinical applications.
{"title":"Quercetin Modulates the Signalling Pathways and Therapeutic Targets in the Pathophysiology of Lung Cancer: A Systematic Review","authors":"M. Farzaei, Seyedsomaye Jasemi, Hosna Khazaei, S. Fakhri, Z. Samimi, I. Aneva","doi":"10.2174/1570180820666230719121525","DOIUrl":"https://doi.org/10.2174/1570180820666230719121525","url":null,"abstract":"\u0000\u0000Lung cancer is a progressive disease with the highest incidence and mortality rate of other cancer types. Besides, the low efficacy of current treatments used against lung cancer urges the need for novel alternative treatments.\u0000\u0000\u0000\u0000Accordingly, quercetin (a flavonoid) has shown a mechanistic-based potential in preventing the progression of lung cancer. So, this study was designed to systematically review quercetin's therapeutic effects on the improvement of lung cancer. For this purpose, PubMed, Scopus and Cochrane library databases were searched based on the keywords lung cancer, lung carcinoma, lung adenocarcinoma and quercetin from 1997 to November 2021. We removed Non-English, repetitive, review and irrelevant articles according to title and abstract in the first step. After that, full-text screening was used to include the final studies.\u0000\u0000\u0000\u0000From a total of 4341 results, finally 36 articles were included in the study, which the whole confirmed the therapeutic effects of quercetin on the improvement of lung malignancy. They also proved that quercetin has a synergic effect with chemical drugs used for lung cancer treatment. From the mechanical point of view, quercetin has employed several signaling mediators for lung therapeutic applications. This systematic review summarizes the modulatory effects of quercetin on several dysregulated pathways, including growth/proliferation, viability, migration/invasion, oxidative stress, inflammation and apoptosis.\u0000\u0000\u0000\u0000Prevailing studies show that quercetin interferes with molecular targets and mechanisms underlying lung cancer to prevent the development of such diseases in clinical applications.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89650920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-19DOI: 10.2174/1570180820666230719121428
Jinsong Chen, Xin Gao, Xiaojuan Man, Bo He, Juan Xiang
Atherosclerosis (AS) is a chronic inflammatory disease characterized by plaque formation and endothelial dysfunction. Under pro-inflammatory conditions, the endothelial-mesenchymal transition (EndMT) plays an important role in the pathogenesis of AS. Resveratrol (RES) is a natural polyphenol in traditional Chinese medicines, which has been proven to possess anti-AS effects. However, the mechanism of RES treating AS through EndMT is not clear at present. RES targets were screened using databases such as SwissTargetPrediction and TargetNet, and AS and EndMT targets were searched using databases such as OMIM and DisGeNET. With the help of Venny 2.1, the key targets were selected by intersection. Next, the protein-protein interaction (PPI) network was constructed through the STRING 11.0 platform and Cytoscape software; gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotations were performed using DAVID. Further, Cytoscape was used to construct a drug-component-gene target-pathway network diagram to identify the core components and genes. Subsequently, an AS rat model was established. The blood lipid level of rats was detected by an automatic biochemical analyzer, and the expression level of the target protein was measured by western blotting. Through network pharmacology analysis, 37 potential targets for RES treating AS and EndMT were identified, and the core targets for RES treating AS consisted of AKT1, TNF, MIMP9, and PPARG. GO enrichment analysis indicated that the treatment of AS with RES mainly involved the migration and proliferation of epithelial and endothelial cells. The KEGG pathway enrichment analysis revealed that the enrichment of TNF and Rap1 signaling pathways was most significant. Besides, RES effectively reduced the levels of total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) in the serum of AS rats, increased the level of high-density lipoprotein cholesterol (HDL-C), and significantly cut down the atherosclerosis index (AI). Twist1, calponin, α-SMA and VE-cadherin were considered as EndMT indexes. The results of the western blot demonstrated that the protein levels of Twist1, calponin and α-SMA were significantly decreased, while the protein expression level of VE-cadherin was notably increased in rats treated with RES. Moreover, RES could also reduce the expression levels of Rap1 and Epac1 proteins. RES is an effective anti-AS drug. Briefly, RES can effectively improve the blood lipid level of AS patients, regulate the expression of EndMT-related proteins, and alleviate the dysfunction of endothelial cells. Notably, the functions of RES are closely associated with the EPAC1-Rap1 pathway.
{"title":"Targets and mechanisms of resveratrol against endothelial-mesenchymal transition in atherosclerosis: A network pharmacology analysis combined with in vivo experiments","authors":"Jinsong Chen, Xin Gao, Xiaojuan Man, Bo He, Juan Xiang","doi":"10.2174/1570180820666230719121428","DOIUrl":"https://doi.org/10.2174/1570180820666230719121428","url":null,"abstract":"\u0000\u0000Atherosclerosis (AS) is a chronic inflammatory disease characterized by plaque formation and endothelial dysfunction. Under pro-inflammatory conditions, the endothelial-mesenchymal transition (EndMT) plays an important role in the pathogenesis of AS. Resveratrol (RES) is a natural polyphenol in traditional Chinese medicines, which has been proven to possess anti-AS effects. However, the mechanism of RES treating AS through EndMT is not clear at present.\u0000\u0000\u0000\u0000RES targets were screened using databases such as SwissTargetPrediction and TargetNet, and AS and EndMT targets were searched using databases such as OMIM and DisGeNET. With the help of Venny 2.1, the key targets were selected by intersection. Next, the protein-protein interaction (PPI) network was constructed through the STRING 11.0 platform and Cytoscape software; gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway annotations were performed using DAVID. Further, Cytoscape was used to construct a drug-component-gene target-pathway network diagram to identify the core components and genes. Subsequently, an AS rat model was established. The blood lipid level of rats was detected by an automatic biochemical analyzer, and the expression level of the target protein was measured by western blotting.\u0000\u0000\u0000\u0000Through network pharmacology analysis, 37 potential targets for RES treating AS and EndMT were identified, and the core targets for RES treating AS consisted of AKT1, TNF, MIMP9, and PPARG. GO enrichment analysis indicated that the treatment of AS with RES mainly involved the migration and proliferation of epithelial and endothelial cells. The KEGG pathway enrichment analysis revealed that the enrichment of TNF and Rap1 signaling pathways was most significant. Besides, RES effectively reduced the levels of total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) in the serum of AS rats, increased the level of high-density lipoprotein cholesterol (HDL-C), and significantly cut down the atherosclerosis index (AI). Twist1, calponin, α-SMA and VE-cadherin were considered as EndMT indexes. The results of the western blot demonstrated that the protein levels of Twist1, calponin and α-SMA were significantly decreased, while the protein expression level of VE-cadherin was notably increased in rats treated with RES. Moreover, RES could also reduce the expression levels of Rap1 and Epac1 proteins.\u0000\u0000\u0000\u0000RES is an effective anti-AS drug. Briefly, RES can effectively improve the blood lipid level of AS patients, regulate the expression of EndMT-related proteins, and alleviate the dysfunction of endothelial cells. Notably, the functions of RES are closely associated with the EPAC1-Rap1 pathway.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89341313","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-19DOI: 10.2174/1570180820666230719121723
Junhua Tan
The chemotherapy medication cisplatin is highly effective and is used in treating a wide variety of cancers. Tumor resistance and dose-related severe side effects, including kidney and hearing damage and suppressed bone marrow function, limit its clinical utility. This study aimed to investigate the nephroprotective effect of alpha-pinene against cisplatin-induced nephrotoxicity in male albino Wistar rats. A total of 24 rats were divided into four groups containing six animals. Alpha-pinene (50 mg/kg) was administered orally for 14 days, and cisplatin (50 mg/kg) was given intraperitoneally for the last two consecutive days (13th and 14th day). Kidney function markers, lipid peroxidative markers, antioxidant status, inflammatory markers, and apoptotic gene expressions were analyzed. The cisplatin-induced rats significantly elevated kidney function markers, inflammatory markers, and pro-apoptotic genes in kidney tissues. Further, the antioxidant level/activities and antiapoptotic gene expression were significantly diminished in cisplatin-induced rats. Pretreatment with alpha-pinene significantly decreased kidney function markers, inflammatory markers, and pro-apoptotic genes and increased antioxidant status and antiapoptotic genes. These findings provide the protective effect of alpha-pinene against CP-induced nephrotoxicity, as measured by potent antioxidant and antiapoptotic properties.
{"title":"Preventive Effect of Alpha-pinene on Cisplatin-induced Kidney Injury by Oxidative Stress, Inflammation and Apoptosis via NF-κB Signaling Pathway","authors":"Junhua Tan","doi":"10.2174/1570180820666230719121723","DOIUrl":"https://doi.org/10.2174/1570180820666230719121723","url":null,"abstract":"\u0000\u0000The chemotherapy medication cisplatin is highly effective and is used in treating a wide variety of cancers. Tumor resistance and dose-related severe side effects, including kidney and hearing damage and suppressed bone marrow function, limit its clinical utility. This study aimed to investigate the nephroprotective effect of alpha-pinene against cisplatin-induced nephrotoxicity in male albino Wistar rats.\u0000\u0000\u0000\u0000A total of 24 rats were divided into four groups containing six animals. Alpha-pinene (50 mg/kg) was administered orally for 14 days, and cisplatin (50 mg/kg) was given intraperitoneally for the last two consecutive days (13th and 14th day). Kidney function markers, lipid peroxidative markers, antioxidant status, inflammatory markers, and apoptotic gene expressions were analyzed. The cisplatin-induced rats significantly elevated kidney function markers, inflammatory markers, and pro-apoptotic genes in kidney tissues. Further, the antioxidant level/activities and antiapoptotic gene expression were significantly diminished in cisplatin-induced rats.\u0000\u0000\u0000\u0000Pretreatment with alpha-pinene significantly decreased kidney function markers, inflammatory markers, and pro-apoptotic genes and increased antioxidant status and antiapoptotic genes.\u0000\u0000\u0000\u0000These findings provide the protective effect of alpha-pinene against CP-induced nephrotoxicity, as measured by potent antioxidant and antiapoptotic properties.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73951609","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-14DOI: 10.2174/1570180820666230714141927
P. M. Gurubasavaraj, Vinodkumar P. Sajjan, Vikram Pujari, S. Inamdar, Nobendu Mukerjee
A new crystalline complex [Ti{La}] has been synthesised in the reaction of titanium butoxide with a phenoxyimine ligand in a 1:1 stoichiometry in toluene at room temperature under a nitrogen atmosphere. The complex has been characterised by various spectroscopic and analytic techniques. A suitable crystal analysed by X-ray diffraction establishes the formation of a stable binuclear μ-oxo-complex with a hexacoordinate titanium centre. The crystal shows a monoclinic system with space group C 1 2/c 1. X-ray crystal structure analysis reveals that this complex has a rhomboidal Ti-O-Ti core and exhibits a C2 symmetric conformation with distorted octahedral geometry. The newly synthesised Ti complex has undergone density functional theory and docking study. Density Functional Theory (DFT) calculations using B3LYP with the basis set of 6-31+G have been performed on the activated species, giving insights into the frontier orbitals and mulliken charge analysis, which showed good correlation with the experimental findings. Additionally, in silico molecular docking of ligand and complex was carried out against the HER2 inhibitor kinase. The complex exhibits a higher binding energy of ΔGb = -19.7 kcal/mol with the active pocket of HER2 (PDB:7JXH) than the ligand ΔGb = -8.5 kcal/mol.
{"title":"Titanium (IV) μ-Oxo Complex Supported by Phenoxyimine Ligand: Synthesis, Crystal Structure Characterisation, DFT and Molecular Docking Studies","authors":"P. M. Gurubasavaraj, Vinodkumar P. Sajjan, Vikram Pujari, S. Inamdar, Nobendu Mukerjee","doi":"10.2174/1570180820666230714141927","DOIUrl":"https://doi.org/10.2174/1570180820666230714141927","url":null,"abstract":"\u0000\u0000A new crystalline complex [Ti{La}] has been synthesised in the reaction of titanium butoxide with a phenoxyimine ligand in a 1:1 stoichiometry in toluene at room temperature under a nitrogen atmosphere. The complex has been characterised by various spectroscopic and analytic techniques. A suitable crystal analysed by X-ray diffraction establishes the formation of a stable binuclear μ-oxo-complex with a hexacoordinate titanium centre. The crystal shows a monoclinic system with space group C 1 2/c 1. X-ray crystal structure analysis reveals that this complex has a rhomboidal Ti-O-Ti core and exhibits a C2 symmetric conformation with distorted octahedral geometry. The newly synthesised Ti complex has undergone density functional theory and docking study. Density Functional Theory (DFT) calculations using B3LYP with the basis set of 6-31+G have been performed on the activated species, giving insights into the frontier orbitals and mulliken charge analysis, which showed good correlation with the experimental findings. Additionally, in silico molecular docking of ligand and complex was carried out against the HER2 inhibitor kinase. The complex exhibits a higher binding energy of ΔGb = -19.7 kcal/mol with the active pocket of HER2 (PDB:7JXH) than the ligand ΔGb = -8.5 kcal/mol.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77755488","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-14DOI: 10.2174/1570180820666230714112516
Krishna K. Singh
Acquired immune deficiency syndrome (HIV/AIDS) has been a major global health concern for over 38 years. No safe and effective preventive or therapeutic vaccine has been developed although many products have been investigated. This computational study was conducted on plant-based active compounds against HIV-1 NEF and p24 protein to obtain and complexes with high binding scores were used for two-dimensional interaction studies via Ligplot to explore hydrogen bond and hydrophobic bond formation. ADMET analysis for best phytocompounds was performed using DruLito, ALOGPS, and PROTOX II. According to the study conducted, phytocompounds like, Protostrychnine, Isostrychnine, Pseudo-Alpha-Colubrine, Alpha-Colubrine, Camptothecin, Benzo[f]quinoline, and (+) -Camptothecin are safe to be considered as a potential drug candidate after experimental validation against NEF and p24 proteins of HIV-1. While, Picrasidine M, Chaetochromin, 3’,3’-Binaringenin, and Sequoiaflavone displayed high binding scores of -10.8, -8.2, -9.5, -9.2 and -9.0, -8.8, -10.6, -9.0 respectively for NEF and p24 protein. All drugs belong to the toxicity class of either 4 or 5. They are inactive for hepatotoxicity and carcinogenicity but active for immunogenicity. For further validation of the results the phytocompounds can be extracted through solvent extraction method and tested on cell lines or animal models for their effectiveness.
{"title":"In-silico Study of Secondary Metabolites as Potential Inhibitors of NEF and P24\u0000Protein of HIV-1","authors":"Krishna K. Singh","doi":"10.2174/1570180820666230714112516","DOIUrl":"https://doi.org/10.2174/1570180820666230714112516","url":null,"abstract":"\u0000\u0000Acquired immune deficiency syndrome (HIV/AIDS) has been a major global health concern for over 38 years. No safe and effective preventive or therapeutic vaccine has been developed although many products have been investigated.\u0000\u0000\u0000\u0000This computational study was conducted on plant-based active compounds against HIV-1 NEF and p24 protein to obtain and complexes with high binding scores were used for two-dimensional interaction studies via Ligplot to explore hydrogen bond and hydrophobic bond formation. ADMET analysis for best phytocompounds was performed using DruLito, ALOGPS, and PROTOX II.\u0000\u0000\u0000\u0000According to the study conducted, phytocompounds like, Protostrychnine, Isostrychnine, Pseudo-Alpha-Colubrine, Alpha-Colubrine, Camptothecin, Benzo[f]quinoline, and (+) -Camptothecin are safe to be considered as a potential drug candidate after experimental validation against NEF and p24 proteins of HIV-1. While, Picrasidine M, Chaetochromin, 3’,3’-Binaringenin, and Sequoiaflavone displayed high binding scores of -10.8, -8.2, -9.5, -9.2 and -9.0, -8.8, -10.6, -9.0 respectively for NEF and p24 protein. All drugs belong to the toxicity class of either 4 or 5. They are inactive for hepatotoxicity and carcinogenicity but active for immunogenicity.\u0000\u0000\u0000\u0000For further validation of the results the phytocompounds can be extracted through solvent extraction method and tested on cell lines or animal models for their effectiveness.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77961814","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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