Pub Date : 2024-01-05DOI: 10.2174/0115701808253017231016041343
Abdullah Haikal, Neelaveni Thangavel, Mohammed Albratty, Asim Najmi, Hassan Ahmed Al Hazmi, Durgaramani Sivadasan, Gulrana Khuwaja, Israa M. Shamkh
Background:: Breast cancer is the most prevalent malignant tumour in women of all races and is the second largest cause of cancer-related death in the majority of races. Based on the pattern of gene expression, five intrinsic or molecular classifications for breast tumours are frequently used. Our research, which is presently being utilized to treat breast cancer and has the potential to significantly change the course of the illness, is focused on two of them: luminal B breast cancer and triplenegative/ basal-like breast cancer. Methods:: Screening a database containing millions of drug molecules or phytochemicals has become rapid and simple due to computer-aided drug design (CADD) techniques. In the current work, nine natural compounds were screened for ambrox from a sperm whale using docking research. Results:: Following docking studies, nine substances were discovered to interact with basal-like and luminal B breast cancer proteins. All nine metabolites, however, adhered to Lipinski's rule of five and had sufficient oral bioavailability. The greatest binding affinities were demonstrated by 13,14,15,16-tetranorlabdane-3-oxo-8,12-diol, 6-β-hydroxy ambrox, 1-α-hydroxy-3-oxoambrox, and 2-α-3-β-dihydroxy ambrox. Conclusion:: Therefore, it can be concluded that research on molecular docking and pharmacological mimics may hasten the discovery of new medications. The use of ambrox metabolites in the treatment of breast cancer also requires future perspectives on their therapeutic use.
背景乳腺癌是所有种族妇女中发病率最高的恶性肿瘤，也是大多数种族中癌症相关死亡的第二大原因。根据基因表达模式，乳腺肿瘤通常有五种内在或分子分类。我们的研究重点是其中的两种：管腔 B 型乳腺癌和三倍体阴性/基底样乳腺癌，目前正用于治疗乳腺癌，并有可能极大地改变乳腺癌的病程。研究方法由于采用了计算机辅助药物设计（CADD）技术，筛选包含数百万药物分子或植物化学物质的数据库变得快速而简单。在目前的工作中，利用对接研究筛选了抹香鲸的九种天然化合物。结果：：经过对接研究，发现九种物质可与基底样和管腔 B 乳腺癌蛋白相互作用。不过，所有九种代谢物都符合利平斯基的五种规则，并具有足够的口服生物利用度。13,14,15,16-tetranorlabdane-3-oxo-8,12-diol、6-β-hydroxy ambrox、1-α-hydroxy-3-oxoambrox 和 2-α-3-β-dihydroxy ambrox 的结合亲和力最强。结论因此，可以得出结论，分子对接和药理模拟研究可能会加速新药的发现。利用氨溴索代谢物治疗乳腺癌还需要对其治疗用途进行展望。
{"title":"In-silico Binding, Stability, Pharmacokinetics, and Toxicity Studies on Natural (-)-ambrox Metabolites as Binding Ligands to Luminal B and Triple- Negative/basal-like Proteins for Breast Cancer Therapy","authors":"Abdullah Haikal, Neelaveni Thangavel, Mohammed Albratty, Asim Najmi, Hassan Ahmed Al Hazmi, Durgaramani Sivadasan, Gulrana Khuwaja, Israa M. Shamkh","doi":"10.2174/0115701808253017231016041343","DOIUrl":"https://doi.org/10.2174/0115701808253017231016041343","url":null,"abstract":"Background:: Breast cancer is the most prevalent malignant tumour in women of all races and is the second largest cause of cancer-related death in the majority of races. Based on the pattern of gene expression, five intrinsic or molecular classifications for breast tumours are frequently used. Our research, which is presently being utilized to treat breast cancer and has the potential to significantly change the course of the illness, is focused on two of them: luminal B breast cancer and triplenegative/ basal-like breast cancer. Methods:: Screening a database containing millions of drug molecules or phytochemicals has become rapid and simple due to computer-aided drug design (CADD) techniques. In the current work, nine natural compounds were screened for ambrox from a sperm whale using docking research. Results:: Following docking studies, nine substances were discovered to interact with basal-like and luminal B breast cancer proteins. All nine metabolites, however, adhered to Lipinski's rule of five and had sufficient oral bioavailability. The greatest binding affinities were demonstrated by 13,14,15,16-tetranorlabdane-3-oxo-8,12-diol, 6-β-hydroxy ambrox, 1-α-hydroxy-3-oxoambrox, and 2-α-3-β-dihydroxy ambrox. Conclusion:: Therefore, it can be concluded that research on molecular docking and pharmacological mimics may hasten the discovery of new medications. The use of ambrox metabolites in the treatment of breast cancer also requires future perspectives on their therapeutic use.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"38 1","pages":""},"PeriodicalIF":1.0,"publicationDate":"2024-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139373453","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-12-12DOI: 10.2174/0115701808239556231121065200
Fangjun Cao, Jian Shen, Hui Zhang, Lu Wang
aims: On this foundation, in this work, we further investigate the therapeutic effects of 2-phenylphthalazin-2-ium bromides on the macrophage-mediated LPS-mediated inflammatory response as well as underlining its molecular mechanisms. background: Quaternary benzo[c]phenanthridine alkaloids (QBAs) have extensively been studied in functions for growth promotion effect and the immune function of the body enhancement, so they have been developed as animal feed additive and attracted the interests of pharmacologists for their very low toxicity to mammals. Meanwhile, quaternary benzo[c]phenanthridine alkaloids such as sanguinarine (SA) and chelerythrine (CH) had been proven to have excellent anti-inflammatory activity. Nevertheless, as potential pant-based antitumor drugs, most of QBAs didn't satisfy our demand for their low content in nature. Thus, it is necessary to develop an effective method to synthesize novel chemical entities with similar structure. Our previous study demonstrated that a novel antifungal 2-phenylphthalazin-2-ium scaffold as a simple analogue was designed and characterized, indicating that they exhibited excellent activity. Most of the compounds showed excellent inhibition activity against almost all eight phytopathogenic fungi, far superior to sanguinarine and chelerythrine. objective: Inspired by quaternary benzo[C]phenanthridine alkaloids, novel 2-phenylphthalazin-2-ium bromides were previously designed and synthesized. The anti-inflammatory effect of 2-phenylphthalazin-2-ium bromides were evaluated based on inflammatory cytokines, and their possible mechanism was explored through NF-κB, TLR4 and MAPK signaling pathways. method: The safe dose range of 2-phenylphthalazin-2-ium bromides was tested by using MTT assay. Griess assay was used to determine the changes of nitric oxide (NO) in the cell culture supernatant. qRT-PCR was used to detect the mRNA levels of inflammatory cytokines, such as IL-6, IL-1ß, IL-10, TNF-α, TLR4 and iNOS. The secretion level of TNF-α and IL-1ß was detected by ELISA. Western blot was used to detect the protein expression of IL-6, IL-10, TLR4, iNOS, NF-κB, p-P38/P38, p-ERK/ERK and p-JNK/JNK. result: 2-(3,5-Dichlorophenyl)phthalazin-2-ium Bromide (2) with a concentration below 1 μg/mL showed no significant effect on the growth inhibition of RAW264.7 cells, so the concentrations of compound 2 used for experiments were set to 0, 0.25, 0.5 and 1 μg/mL. Compared with the blank control group, the model group showed increased release of NO, transcription levels of IL-6, IL-1ß, IL-10, TNF-α, TLR4 and iNOS (P<0.05), and ratios of p-P38/P38, p-ERK/ERK, p-JNK/JNK (P<0.05). Compared with model group, sample groups displayed decreased NO release and reduced transcriptional levels of IL-6, IL-1ß, IL-10, TNF-α, TLR4, iNOS and reducing protein expression ratios of IL-6, IL-1ß, IL-10, TNF-α, NF-κB, TLR4, iNOS, p-P38/P38, p-ERK/ERK and p-JNK/JNK (P<0.05). conclusion: This study showed that 2-phenylp
{"title":"Anti-inflammatory Effect of Novel 2-Phenylphthalazin-2-ium Bromides on LPS-induced RAW264.7 Cells and their Mechanism","authors":"Fangjun Cao, Jian Shen, Hui Zhang, Lu Wang","doi":"10.2174/0115701808239556231121065200","DOIUrl":"https://doi.org/10.2174/0115701808239556231121065200","url":null,"abstract":"aims: On this foundation, in this work, we further investigate the therapeutic effects of 2-phenylphthalazin-2-ium bromides on the macrophage-mediated LPS-mediated inflammatory response as well as underlining its molecular mechanisms. background: Quaternary benzo[c]phenanthridine alkaloids (QBAs) have extensively been studied in functions for growth promotion effect and the immune function of the body enhancement, so they have been developed as animal feed additive and attracted the interests of pharmacologists for their very low toxicity to mammals. Meanwhile, quaternary benzo[c]phenanthridine alkaloids such as sanguinarine (SA) and chelerythrine (CH) had been proven to have excellent anti-inflammatory activity. Nevertheless, as potential pant-based antitumor drugs, most of QBAs didn't satisfy our demand for their low content in nature. Thus, it is necessary to develop an effective method to synthesize novel chemical entities with similar structure. Our previous study demonstrated that a novel antifungal 2-phenylphthalazin-2-ium scaffold as a simple analogue was designed and characterized, indicating that they exhibited excellent activity. Most of the compounds showed excellent inhibition activity against almost all eight phytopathogenic fungi, far superior to sanguinarine and chelerythrine. objective: Inspired by quaternary benzo[C]phenanthridine alkaloids, novel 2-phenylphthalazin-2-ium bromides were previously designed and synthesized. The anti-inflammatory effect of 2-phenylphthalazin-2-ium bromides were evaluated based on inflammatory cytokines, and their possible mechanism was explored through NF-κB, TLR4 and MAPK signaling pathways. method: The safe dose range of 2-phenylphthalazin-2-ium bromides was tested by using MTT assay. Griess assay was used to determine the changes of nitric oxide (NO) in the cell culture supernatant. qRT-PCR was used to detect the mRNA levels of inflammatory cytokines, such as IL-6, IL-1ß, IL-10, TNF-α, TLR4 and iNOS. The secretion level of TNF-α and IL-1ß was detected by ELISA. Western blot was used to detect the protein expression of IL-6, IL-10, TLR4, iNOS, NF-κB, p-P38/P38, p-ERK/ERK and p-JNK/JNK. result: 2-(3,5-Dichlorophenyl)phthalazin-2-ium Bromide (2) with a concentration below 1 μg/mL showed no significant effect on the growth inhibition of RAW264.7 cells, so the concentrations of compound 2 used for experiments were set to 0, 0.25, 0.5 and 1 μg/mL. Compared with the blank control group, the model group showed increased release of NO, transcription levels of IL-6, IL-1ß, IL-10, TNF-α, TLR4 and iNOS (P&lt;0.05), and ratios of p-P38/P38, p-ERK/ERK, p-JNK/JNK (P&lt;0.05). Compared with model group, sample groups displayed decreased NO release and reduced transcriptional levels of IL-6, IL-1ß, IL-10, TNF-α, TLR4, iNOS and reducing protein expression ratios of IL-6, IL-1ß, IL-10, TNF-α, NF-κB, TLR4, iNOS, p-P38/P38, p-ERK/ERK and p-JNK/JNK (P&lt;0.05). conclusion: This study showed that 2-phenylp","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"17 1","pages":""},"PeriodicalIF":1.0,"publicationDate":"2023-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138579289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-29DOI: 10.2174/0115701808274195231113053944
T. Hatakenaka, Y. Fujimoto, K. Okamoto, T. Kato
Background: Numerous inhibitory peptides against angiotensin I-converting enzyme, a target for hypertension treatment, have been found in previous studies. Recently, machine learning screening has been employed to predict unidentified inhibitory peptides using a database of known inhibitory peptides and descriptor data from docking simulations. Objective: The aim of this study is to focus on angiotensin I-converting enzyme inhibitory tripeptides containing proline, to predict novel inhibitory peptides using the machine learning algorithm PyCaret based on their IC50 and descriptors from docking simulations, and to validate the screening method by machine learning by comparing the results with in vitro inhibitory activity studies. Methods: IC50 of known inhibitory peptides were collected from an online database, and descriptor data were summarized by docking simulations. Candidate inhibitory peptides were predicted from these data using the PyCaret. Candidate tripeptides were synthesized by solid-phase synthesis and their inhibitory activity was measured in vitro. Results: Seven novel tripeptides were found from the peptides predicted to have high inhibitory activity by machine learning, and these peptides were synthesized and evaluated for inhibitory activity in vitro. As a result, the proline-containing tripeptide MPA showed high inhibitory activity, with an IC50 value of 8.6 µM. Conclusion: In this study, we identified a proline-containing tripeptide with high ACE inhibitory activity among the candidates predicted by machine learning. This finding indicates that the method of predicting by machine learning is promising for future inhibitory peptide screening efforts.
{"title":"Prediction and Validation of Proline-containing Tripeptides with Angiotensin I-converting Enzyme Inhibitory Activity Using Machine Learning Models","authors":"T. Hatakenaka, Y. Fujimoto, K. Okamoto, T. Kato","doi":"10.2174/0115701808274195231113053944","DOIUrl":"https://doi.org/10.2174/0115701808274195231113053944","url":null,"abstract":"Background: Numerous inhibitory peptides against angiotensin I-converting enzyme, a target for hypertension treatment, have been found in previous studies. Recently, machine learning screening has been employed to predict unidentified inhibitory peptides using a database of known inhibitory peptides and descriptor data from docking simulations. Objective: The aim of this study is to focus on angiotensin I-converting enzyme inhibitory tripeptides containing proline, to predict novel inhibitory peptides using the machine learning algorithm PyCaret based on their IC50 and descriptors from docking simulations, and to validate the screening method by machine learning by comparing the results with in vitro inhibitory activity studies. Methods: IC50 of known inhibitory peptides were collected from an online database, and descriptor data were summarized by docking simulations. Candidate inhibitory peptides were predicted from these data using the PyCaret. Candidate tripeptides were synthesized by solid-phase synthesis and their inhibitory activity was measured in vitro. Results: Seven novel tripeptides were found from the peptides predicted to have high inhibitory activity by machine learning, and these peptides were synthesized and evaluated for inhibitory activity in vitro. As a result, the proline-containing tripeptide MPA showed high inhibitory activity, with an IC50 value of 8.6 µM. Conclusion: In this study, we identified a proline-containing tripeptide with high ACE inhibitory activity among the candidates predicted by machine learning. This finding indicates that the method of predicting by machine learning is promising for future inhibitory peptide screening efforts.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"70 1","pages":""},"PeriodicalIF":1.0,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138529378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background:: Since renal ischemia-reperfusion (I/R) can lead to a serious health problem, aquaporins have important roles in preventing negative changes in electrolyte-water balance. This study aimed to determine the effect of naringin treatment on renal function and AQP1 and AQP2 levels in the kidney cortex and medulla tissues in experimental renal I/R in rats. Method and Material: The study was carried out on 40 male Wistar-type rats, 8-12 weeks old. Experimental groups were formed as follows: 1) Control, 2) Sham+vehicle, 3) Renal (I/R)+vehicle, 4) Renal I/R+ Naringin (50mg/kg/day) (3 days of administration), and 5) Renal I/R+ Naringin( 100mg/kg/day) (3 days supplementation) group. First, the left kidney was removed by nephrectomy under general anesthesia, and then the right kidney was subjected to 45 minutes of ischemia and then 72 hours of reperfusion. Naringin was given to the experimental animals by an intraperitoneal route at the beginning of the reperfusion, after 24 and 48 hours. At the end of the experiments, first of all, blood samples were taken from the heart in animals under general anesthesia, and then the animals were killed by cervical dislocation, and kidney tissue samples were taken. Osmolarity in plasma and urine and plasma creatinine levels were evaluated. AQP1 and AQP2 levels were analyzed in the kidney cortex and medulla tissues by ELISA and PCR methods. Result:: In kidney tissues, I/R led to a decrease in plasma and urinary osmolality, AQP1 and AQP2 levels in the cortex and medulla, and an increase in urea and creatinine levels (p < 0.001). However, naringin supplementation corrected the deterioration to a certain extent. Conclusion:: The results of the study show that naringin supplementation at different doses, such as 50 or 100 mg/kg, may have protective effects on the deterioration of renal function caused by unilateral nephrectomy and I/R in rats.
{"title":"Short-term Administration of Naringin Improves Renal Function in Renal Ischemia-reperfusion by Increasing Aquaporin-1 and Aquaporin-2 Levels","authors":"Zubeyde Demir, Gozde Acar, Dervis Dasdelen, Rasim Mogulkoc, Abdulkerim Kasim Baltaci","doi":"10.2174/0115701808271000231120094951","DOIUrl":"https://doi.org/10.2174/0115701808271000231120094951","url":null,"abstract":"Background:: Since renal ischemia-reperfusion (I/R) can lead to a serious health problem, aquaporins have important roles in preventing negative changes in electrolyte-water balance. This study aimed to determine the effect of naringin treatment on renal function and AQP1 and AQP2 levels in the kidney cortex and medulla tissues in experimental renal I/R in rats. Method and Material: The study was carried out on 40 male Wistar-type rats, 8-12 weeks old. Experimental groups were formed as follows: 1) Control, 2) Sham+vehicle, 3) Renal (I/R)+vehicle, 4) Renal I/R+ Naringin (50mg/kg/day) (3 days of administration), and 5) Renal I/R+ Naringin( 100mg/kg/day) (3 days supplementation) group. First, the left kidney was removed by nephrectomy under general anesthesia, and then the right kidney was subjected to 45 minutes of ischemia and then 72 hours of reperfusion. Naringin was given to the experimental animals by an intraperitoneal route at the beginning of the reperfusion, after 24 and 48 hours. At the end of the experiments, first of all, blood samples were taken from the heart in animals under general anesthesia, and then the animals were killed by cervical dislocation, and kidney tissue samples were taken. Osmolarity in plasma and urine and plasma creatinine levels were evaluated. AQP1 and AQP2 levels were analyzed in the kidney cortex and medulla tissues by ELISA and PCR methods. Result:: In kidney tissues, I/R led to a decrease in plasma and urinary osmolality, AQP1 and AQP2 levels in the cortex and medulla, and an increase in urea and creatinine levels (p < 0.001). However, naringin supplementation corrected the deterioration to a certain extent. Conclusion:: The results of the study show that naringin supplementation at different doses, such as 50 or 100 mg/kg, may have protective effects on the deterioration of renal function caused by unilateral nephrectomy and I/R in rats.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"9 7","pages":""},"PeriodicalIF":1.0,"publicationDate":"2023-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138509983","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-22DOI: 10.2174/0115701808247887231110112551
Amir Asadi, Ali Mandegary, Mostafa Pournamdari, Mahboobe Abbasi, Neda Mohamadi, Fariba Sharififar
Antinociceptive effect of fenugreek seeds (Trigonella foenum-graecum L.) has been reported in different animal models in response to various chemical or thermal stimuli. In a recent study, alkaline chloroform fraction (AKC) of this plant has exhibited the greatest analgesic effect. In the present study, to isolate the active component(s) from the plant, the subfractions resulting from AKC column chromatography were evaluated in an animal model for anti-nociception effect. From the 17 separated fractions, 5 major fractions (F4, F6, F14, F15 and F16) were used for the formalin test at three different doses (2.5, 5 10 mg/kg). Antioxidant activity of the most active subfractions was studied too. Subsections F16 and F14 (5, 10 mg/kg) showed the greatest analgesic effect and reduced, which was similar to morphine and even stronger than morphine in some doses. The greatest antioxidant activity was observed by F14 (radical inhibition percentage of 17.34± 0.14 in DPPH assay, reduction power percentage of 74.05±4.23 in RPA versus green tea (91.68± 3.04 and 97.59± 6.24 in DPPH assay and RPA test respectively). The absorbance of F14 was 0.25±0.11 in the FTC method in comparison to ascorbic acid 10 μg/ml and 100 μg/ml (0.72±0.33 and 0.05±0.41 respectively). Separated subfractions exhibited more antinociceptive effect than AKC fraction, so further separation can lead to the acquisition of antinociceptive compound (s), while AKC fraction was found to be more potent antioxidant than separated sub-fractions in all three experiments. So, most likely, the anti-nociception effect of subfractions might be achieved via other mechanisms than antioxidant activity. Based on phytochemical screening, AKC and all sub-fractions especially F14, F15 and F16 were positive for the presence of alkaloids and only F14 was positive for flavonoids.
{"title":"Bioactivity-guided Separation of Antinociceptive and Antioxidant Subfractions from Alkaline Chloroform Fraction of Fenugreek Seeds (Trigonella foenum-graecum L.) in an Animal Model","authors":"Amir Asadi, Ali Mandegary, Mostafa Pournamdari, Mahboobe Abbasi, Neda Mohamadi, Fariba Sharififar","doi":"10.2174/0115701808247887231110112551","DOIUrl":"https://doi.org/10.2174/0115701808247887231110112551","url":null,"abstract":"Antinociceptive effect of fenugreek seeds (Trigonella foenum-graecum L.)\u0000has been reported in different animal models in response to various chemical or thermal stimuli. In a\u0000recent study, alkaline chloroform fraction (AKC) of this plant has exhibited the greatest analgesic\u0000effect.\u0000\u0000\u0000\u0000In the present study, to isolate the active component(s) from the plant, the subfractions\u0000resulting from AKC column chromatography were evaluated in an animal model for anti-nociception\u0000effect.\u0000\u0000\u0000\u0000From the 17 separated fractions, 5 major fractions (F4, F6, F14, F15 and F16) were used for\u0000the formalin test at three different doses (2.5, 5 10 mg/kg). Antioxidant activity of the most active\u0000subfractions was studied too.\u0000\u0000\u0000\u0000Subsections F16 and F14 (5, 10 mg/kg) showed the greatest analgesic effect and reduced,\u0000which was similar to morphine and even stronger than morphine in some doses. The greatest antioxidant\u0000activity was observed by F14 (radical inhibition percentage of 17.34± 0.14 in DPPH assay, reduction\u0000power percentage of 74.05±4.23 in RPA versus green tea (91.68± 3.04 and 97.59± 6.24 in\u0000DPPH assay and RPA test respectively). The absorbance of F14 was 0.25±0.11 in the FTC method in\u0000comparison to ascorbic acid 10 μg/ml and 100 μg/ml (0.72±0.33 and 0.05±0.41 respectively).\u0000\u0000\u0000\u0000Separated subfractions exhibited more antinociceptive effect than AKC fraction, so\u0000further separation can lead to the acquisition of antinociceptive compound (s), while AKC fraction\u0000was found to be more potent antioxidant than separated sub-fractions in all three experiments. So,\u0000most likely, the anti-nociception effect of subfractions might be achieved via other mechanisms than\u0000antioxidant activity. Based on phytochemical screening, AKC and all sub-fractions especially F14,\u0000F15 and F16 were positive for the presence of alkaloids and only F14 was positive for flavonoids.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"23 3 1","pages":""},"PeriodicalIF":1.0,"publicationDate":"2023-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138529370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-08DOI: 10.2174/0115701808260478231023080842
Carlos Polanco, Alberto Huberman, Enrique Hernandez Lemus, Vladimir N. Uversky, Martha Rios Castro, Mireya Martinez Garcia, Gilberto Vargas-Alarcon, Thomas Buhse, Claudia Pimentel Hernández, Cecilia Zazueta, Francisco J. Roldan Gomez, Erika Jeannette López Oliva
Background:: Previously restricted to remote areas of Central and Western Africa, the MPOX virus-based disease, also known as monkeypox, has now spread to more than 90 countries and has become endemic. As a consequence, the MPOX virus has become a global public health concern. Objective:: The objective of this study was to conduct a computational-multiparametric study (at the genomic and proteomic levels) of the biological sequences that express the MPOX virus envelopes in order to fathom the physicochemical regularities of these proteins. objective: To carry out a computational multiparametric analysis of the amino acid sequences of proteins expressed by the MPOX virus genes to better understand the physicochemical regularities of these proteins Methods:: Using computer programs, we determined the polarity index method (PIM) profile and protein intrinsic disorder predisposition (PIDP) for each studied protein. Results:: The UniProt database was able to identify sequences similar to those of the MPOX virus expressed thanks to the computational regularities found in the virus' envelope sequences. Conclusion:: The polarity index method and protein intrinsic disorder predisposition profiles could aid in elucidating the sequence-level structural regularities of the MPOX virus envelopes.
{"title":"Bioinformatics-based Analysis of the Variability of MPOX Virus Proteins","authors":"Carlos Polanco, Alberto Huberman, Enrique Hernandez Lemus, Vladimir N. Uversky, Martha Rios Castro, Mireya Martinez Garcia, Gilberto Vargas-Alarcon, Thomas Buhse, Claudia Pimentel Hernández, Cecilia Zazueta, Francisco J. Roldan Gomez, Erika Jeannette López Oliva","doi":"10.2174/0115701808260478231023080842","DOIUrl":"https://doi.org/10.2174/0115701808260478231023080842","url":null,"abstract":"Background:: Previously restricted to remote areas of Central and Western Africa, the MPOX virus-based disease, also known as monkeypox, has now spread to more than 90 countries and has become endemic. As a consequence, the MPOX virus has become a global public health concern. Objective:: The objective of this study was to conduct a computational-multiparametric study (at the genomic and proteomic levels) of the biological sequences that express the MPOX virus envelopes in order to fathom the physicochemical regularities of these proteins. objective: To carry out a computational multiparametric analysis of the amino acid sequences of proteins expressed by the MPOX virus genes to better understand the physicochemical regularities of these proteins Methods:: Using computer programs, we determined the polarity index method (PIM) profile and protein intrinsic disorder predisposition (PIDP) for each studied protein. Results:: The UniProt database was able to identify sequences similar to those of the MPOX virus expressed thanks to the computational regularities found in the virus' envelope sequences. Conclusion:: The polarity index method and protein intrinsic disorder predisposition profiles could aid in elucidating the sequence-level structural regularities of the MPOX virus envelopes.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"17 4","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135430184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-07DOI: 10.2174/0115701808248646231102075104
Mohammad Reza Mahdinezhad, Farshad Mirzavi, Sara Hooshmand, Shirin Taraz Jamshidi, Ahmad Ghorbani, Mohammad Soukhtanloo
Background:: Consumption of a high-fat diet (HFD) is one of the main causes of nonalcoholic fatty liver disease (NAFLD), which is increasing due to lifestyle changes and is still an important global health issue. Despite the efforts, there is still no common treatment for this disease. Studies have shown that the root of Rheum turkestanicum Janisch has a hypolipidemic effect and a significant antioxidant effect on liver tissue in diabetic rats. However, no experimental study has been performed on the hepatoprotective effects of this herb on HFD-induced NAFLD have been proven. background: Consumption of a high-fat diet (HFD) is one of the main causes of non-alcoholic fatty liver disease (NAFLD), which is increasing due to lifestyle changes and is still an important global health issue. Despite the efforts, there is still no common treatment for this disease. Studies have shown that the root of Rheum turkestanicum Janisch has a hypolipidemic effect and a significant antioxidant effect on liver tissue in diabetic rats. However, no experimental study has been performed on which the hepatoprotective effects of this herb on HFD-induced NAFLD have been proven. Objective:: This study aimed to evaluate the effect of Rheum turkestanicum Janisch extract (RTE) on HFD-induced NAFLD in BALB/c mice. Materials and Methods:: The study was performed with two models of prevention and therapeutic effect of RTE. Serum biochemical markers, histopathology, oxidative stress indicators, and qRTPCR were measured to evaluate the effects of RTE on lipid metabolism disorders in mice feeding with HFD. Results:: In the prevention model, compared to the HFD group, RTE treatment decreased the levels of glucose, triglyceride, and cholesterol and improved liver profile markers, oxidative stress, and expression of genes involved in lipid metabolism. Conclusion:: The results of this study suggest that RTE has hepatoprotective effects against HFDinduced liver damage by reducing oxidative stress, lipogenesis, and increasing beta-oxidation of free fatty acids.
{"title":"Hepatoprotective Effects of Rheum turkestanicum Janisch on High-fat Diet-induced Non-alcoholic Fatty Liver Disease in Mice","authors":"Mohammad Reza Mahdinezhad, Farshad Mirzavi, Sara Hooshmand, Shirin Taraz Jamshidi, Ahmad Ghorbani, Mohammad Soukhtanloo","doi":"10.2174/0115701808248646231102075104","DOIUrl":"https://doi.org/10.2174/0115701808248646231102075104","url":null,"abstract":"Background:: Consumption of a high-fat diet (HFD) is one of the main causes of nonalcoholic fatty liver disease (NAFLD), which is increasing due to lifestyle changes and is still an important global health issue. Despite the efforts, there is still no common treatment for this disease. Studies have shown that the root of Rheum turkestanicum Janisch has a hypolipidemic effect and a significant antioxidant effect on liver tissue in diabetic rats. However, no experimental study has been performed on the hepatoprotective effects of this herb on HFD-induced NAFLD have been proven. background: Consumption of a high-fat diet (HFD) is one of the main causes of non-alcoholic fatty liver disease (NAFLD), which is increasing due to lifestyle changes and is still an important global health issue. Despite the efforts, there is still no common treatment for this disease. Studies have shown that the root of Rheum turkestanicum Janisch has a hypolipidemic effect and a significant antioxidant effect on liver tissue in diabetic rats. However, no experimental study has been performed on which the hepatoprotective effects of this herb on HFD-induced NAFLD have been proven. Objective:: This study aimed to evaluate the effect of Rheum turkestanicum Janisch extract (RTE) on HFD-induced NAFLD in BALB/c mice. Materials and Methods:: The study was performed with two models of prevention and therapeutic effect of RTE. Serum biochemical markers, histopathology, oxidative stress indicators, and qRTPCR were measured to evaluate the effects of RTE on lipid metabolism disorders in mice feeding with HFD. Results:: In the prevention model, compared to the HFD group, RTE treatment decreased the levels of glucose, triglyceride, and cholesterol and improved liver profile markers, oxidative stress, and expression of genes involved in lipid metabolism. Conclusion:: The results of this study suggest that RTE has hepatoprotective effects against HFDinduced liver damage by reducing oxidative stress, lipogenesis, and increasing beta-oxidation of free fatty acids.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"71 S2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135544792","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-02DOI: 10.2174/0115701808241753231024111800
Sonia Chauhan, Sakshi Sharma, Rupa Mazumder, Nidhi Sharma
Background: Inflammatory bowel disease is a chronic relapsing disorder that causes chronic inflammation and ulcers in the GIT. Depending upon the location, ulcerative colitis and Crohn's disease come under IBD. The exact etiology of IBD is still unknown. Over 8 lakhs of people were affected by inflammatory disease yearly, and the death rate increased daily. Depending upon the severity of the disease, JAK inhibitors, anti-TNF agents, and immunosuppressants can be used to manage ulcerative colitis and Crohn's disease. However, these treatments have been associated with harmful adverse effects, which cannot be ignored. Methods: To treat inflammatory diseases safely, various herbal medicines and their bioactive are preferred as game changers. Recently, the effectiveness of herbal plants has been recommended as the treatment against IBD, as shown by various in vivo models and clinical trials. The various herbal plants reported in the literature include gallic acid, lupeol, and curcumin aloe vera. Result: This review focused on medicinal plants' anti-inflammatory, antioxidant, and anti-ulcer properties. Over 1.2 million healthcare practitioners are using herbal bioactive and have the advantages of lower side effects. Conclusion: Therefore, it is estimated that in Europe, the demand for plant-based products/formulations has risen by millions in 2020, showing the current position of herbal-based products in consumer health awareness.
{"title":"Bioactive Natural Leads and Traditional Herbal Plants in the Management of Inflammatory Bowel Diseases: A Brief Review","authors":"Sonia Chauhan, Sakshi Sharma, Rupa Mazumder, Nidhi Sharma","doi":"10.2174/0115701808241753231024111800","DOIUrl":"https://doi.org/10.2174/0115701808241753231024111800","url":null,"abstract":"Background: Inflammatory bowel disease is a chronic relapsing disorder that causes chronic inflammation and ulcers in the GIT. Depending upon the location, ulcerative colitis and Crohn's disease come under IBD. The exact etiology of IBD is still unknown. Over 8 lakhs of people were affected by inflammatory disease yearly, and the death rate increased daily. Depending upon the severity of the disease, JAK inhibitors, anti-TNF agents, and immunosuppressants can be used to manage ulcerative colitis and Crohn's disease. However, these treatments have been associated with harmful adverse effects, which cannot be ignored. Methods: To treat inflammatory diseases safely, various herbal medicines and their bioactive are preferred as game changers. Recently, the effectiveness of herbal plants has been recommended as the treatment against IBD, as shown by various in vivo models and clinical trials. The various herbal plants reported in the literature include gallic acid, lupeol, and curcumin aloe vera. Result: This review focused on medicinal plants' anti-inflammatory, antioxidant, and anti-ulcer properties. Over 1.2 million healthcare practitioners are using herbal bioactive and have the advantages of lower side effects. Conclusion: Therefore, it is estimated that in Europe, the demand for plant-based products/formulations has risen by millions in 2020, showing the current position of herbal-based products in consumer health awareness.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"7 2","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135974638","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-11-01DOI: 10.2174/1570180819666220818145647
Jiaojiao Li, Lin Zhu, Zheng Qin, Zhengfu Li, Xun Gao, Jing Ji, Jinyang Shen
Background: The COVID-19 outbreak is a serious concern and has caused a great loss to the global economy. Therefore, COVID-19 has become an urgent public health problem. Although new vaccines and small molecule drugs are now available, these prevention and treatment methods cannot completely control the epidemic due to the constant mutation of SARS-CoV-2. Targeting 3CLpro/RdRp is expected to develop drugs that are not susceptible to the mutation of SARS-COV-2, and it will also have a certain effect on the coronavirus that may appear in the future. Objective: This study aimed to find small molecules against SARS-CoV-2 with research potential and provide relevant data for the rational development of anti-SARS-COV-2 drugs. Methods: Targeting 3CLpro/RdRp, using Shards database (120,000 natural small molecule compounds) in the ZINC database, adopting a step-by-step screening strategy, and taking Lopinavir, Indinavir, and Molnupiravir as screening criteria was done. Moreover, the top scoring compounds were screened using rigid docking, and molecular dynamics simulation and ADME prediction were performed. Finally, the molecules with better scores were screened out. Results: After molecular docking with 3CLpro as the target, 3207 compounds meeting the screening criteria were obtained. After applying Lipinski's rule of five for drug property screening, 1825 compounds that met the criteria were obtained. After molecular docking with RdRp as the target, ZINC04259665 has a good docking score. According to molecular dynamics simulation results, ZINC04259665 is stable in combination with 3CLpro/RdRp. ADME prediction shows that ZINC04259665 has good druggability. Conclusion: Using 3CLpro/RdRp targets and then using a step-by-step strategy to screen the compound with the highest score through molecular dynamics simulation and ADME prediction, it was found that ZINC04259665 has good development potential and can be used as a follow-up hit compound for research. In addition, the data obtained provide relevant information for the rational development of anti- SARS-COV-2 drugs.
{"title":"Discovery of Potential Compounds Against SARS-CoV-2 Based on 3CLpro/RdRp Dual-target: An In silico Approach","authors":"Jiaojiao Li, Lin Zhu, Zheng Qin, Zhengfu Li, Xun Gao, Jing Ji, Jinyang Shen","doi":"10.2174/1570180819666220818145647","DOIUrl":"https://doi.org/10.2174/1570180819666220818145647","url":null,"abstract":"Background: The COVID-19 outbreak is a serious concern and has caused a great loss to the global economy. Therefore, COVID-19 has become an urgent public health problem. Although new vaccines and small molecule drugs are now available, these prevention and treatment methods cannot completely control the epidemic due to the constant mutation of SARS-CoV-2. Targeting 3CLpro/RdRp is expected to develop drugs that are not susceptible to the mutation of SARS-COV-2, and it will also have a certain effect on the coronavirus that may appear in the future. Objective: This study aimed to find small molecules against SARS-CoV-2 with research potential and provide relevant data for the rational development of anti-SARS-COV-2 drugs. Methods: Targeting 3CLpro/RdRp, using Shards database (120,000 natural small molecule compounds) in the ZINC database, adopting a step-by-step screening strategy, and taking Lopinavir, Indinavir, and Molnupiravir as screening criteria was done. Moreover, the top scoring compounds were screened using rigid docking, and molecular dynamics simulation and ADME prediction were performed. Finally, the molecules with better scores were screened out. Results: After molecular docking with 3CLpro as the target, 3207 compounds meeting the screening criteria were obtained. After applying Lipinski's rule of five for drug property screening, 1825 compounds that met the criteria were obtained. After molecular docking with RdRp as the target, ZINC04259665 has a good docking score. According to molecular dynamics simulation results, ZINC04259665 is stable in combination with 3CLpro/RdRp. ADME prediction shows that ZINC04259665 has good druggability. Conclusion: Using 3CLpro/RdRp targets and then using a step-by-step strategy to screen the compound with the highest score through molecular dynamics simulation and ADME prediction, it was found that ZINC04259665 has good development potential and can be used as a follow-up hit compound for research. In addition, the data obtained provide relevant information for the rational development of anti- SARS-COV-2 drugs.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"329 ","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136103073","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background:: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) plays a crucial role in regulating lipid and glucose metabolism, cancer, and inflammation, making it an attractive target for drug development. Meanwhile, β-Carotene, known for its antioxidant, anticancer and antiinflammatory properties, holds promise for modulating PPAR-γ activity. Understanding their interaction is crucial. Objective:: This study aims to explore the therapeutic potential of β-carotene in modulating PPAR-γ activity by investigating their binding interactions. objective: To explore the potential therapeutic applications of β-carotene in modulating PPAR-γ activity, it is of great interest to comprehend the binding interactions between PPAR-γ and β-carotene. Methods:: Screening of bioactive compounds from PubChem was conducted using GlideXP to identify potential PPAR-γ (PDB: 2PRG) ligands. During this screening, both protein and bioactive compounds were prepared following established protocols. Subsequently, the compounds were docked into the ligand binding domain (LBD) of the protein using XP docking. Rosiglitazone was used as an internal control. β-Carotene emerged as a lead based on Lipinski’s rule, docking score, free energy, and LBD interactions. Molinspiration analysis assessed its drug likeness. Molecular dynamics (MD) simulations utilizing Desmond with OPLS 2005 force field were employed to examine the dynamics and stability of the PPAR-γ/β-carotene complex. Results:: β-carotene had strong hydrophobic interactions with specific residues within the ligandbinding domain of PPAR-γ. The calculated binding affinity (-9.07 kcal/mol) indicated a strong interaction between β-carotene and PPAR-γ, suggesting that β-carotene may modulate the activity of PPAR-γ. On a time scale of 100 ns, the MD simulations provided insights into the conformational changes, flexibility, and intermolecular interactions within the complex. Conclusion:: In silico docking and dynamics simulation analyses show that PPAR-γ and β-carotene can form a stable complex, suggesting potential implications for metabolic modulation.
{"title":"In-silico Docking and Dynamics Simulation Analysis of Peroxisome Proliferator-Activated Receptor-Gamma and β-Carotene","authors":"Divya Jindal, Parasuraman Aiya Subramani, Kalpana Panati, Praveen Kumar Pasala, Rajeswara Reddy Saddala, Venkata Ramireddy Narala","doi":"10.2174/0115701808267878231026044212","DOIUrl":"https://doi.org/10.2174/0115701808267878231026044212","url":null,"abstract":"Background:: Peroxisome proliferator-activated receptor-gamma (PPAR-γ) plays a crucial role in regulating lipid and glucose metabolism, cancer, and inflammation, making it an attractive target for drug development. Meanwhile, β-Carotene, known for its antioxidant, anticancer and antiinflammatory properties, holds promise for modulating PPAR-γ activity. Understanding their interaction is crucial. Objective:: This study aims to explore the therapeutic potential of β-carotene in modulating PPAR-γ activity by investigating their binding interactions. objective: To explore the potential therapeutic applications of β-carotene in modulating PPAR-γ activity, it is of great interest to comprehend the binding interactions between PPAR-γ and β-carotene. Methods:: Screening of bioactive compounds from PubChem was conducted using GlideXP to identify potential PPAR-γ (PDB: 2PRG) ligands. During this screening, both protein and bioactive compounds were prepared following established protocols. Subsequently, the compounds were docked into the ligand binding domain (LBD) of the protein using XP docking. Rosiglitazone was used as an internal control. β-Carotene emerged as a lead based on Lipinski’s rule, docking score, free energy, and LBD interactions. Molinspiration analysis assessed its drug likeness. Molecular dynamics (MD) simulations utilizing Desmond with OPLS 2005 force field were employed to examine the dynamics and stability of the PPAR-γ/β-carotene complex. Results:: β-carotene had strong hydrophobic interactions with specific residues within the ligandbinding domain of PPAR-γ. The calculated binding affinity (-9.07 kcal/mol) indicated a strong interaction between β-carotene and PPAR-γ, suggesting that β-carotene may modulate the activity of PPAR-γ. On a time scale of 100 ns, the MD simulations provided insights into the conformational changes, flexibility, and intermolecular interactions within the complex. Conclusion:: In silico docking and dynamics simulation analyses show that PPAR-γ and β-carotene can form a stable complex, suggesting potential implications for metabolic modulation.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"3 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135977585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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