Pub Date : 2023-08-31DOI: 10.2174/1570180820666230831095954
Berlin Grace V M, R. Ravichandran, David Wilson D, S. Viswanathan, Siddikuzzaman, Lucia Bonati, R. Selvamani
The activated oncogenic Notch signalling is an emerging target to treat cancer progression and recurrence. Synthetic inhibitors of Notch receptors are in pre-clinical studies. However, the overexpression of Notch signalling molecules at the gene level needs to be regulated to control cancer progression. We propose that this can be achieved by gene-regulatory drugs in combination with natural phytochemical compounds. The ethanol extract of Allium sativum alone and in combination with DAPT and ATRA were evaluated for cytotoxicity on A549 cells by MTT and Trypan blue assays. Their effects on Notch 1, Hes 1 and p53 gene expressions were studied by RT-PCR and qPCR. Their inhibition on metastatic invasion of A549 cells was analyzed by in vitro wound scratch assay. The phytochemicals of the extract were identified by GC-MS analysis. Many organosulfur compounds having anti-cancer potency were identified in GC-MS. The combination treatment with 50µg (IC50) of garlic extract exhibited a highly significant (P≤0.01) synergistic inhibitory effect on A549 cell growth and migration. It has also significantly reduced the expression of Notch 1 and Hes 1 oncogenes and enhanced p53 gene expression, compared with the individual treatments. This indicates the synergistic action of the extract on the downregulation of Notch signalling at the mRNA level. Our study results imply that the combination therapies have potent molecular treatment action via down-regulating Notch signaling target genes and upregulating p53 gene expression as an underlying mechanism of inhibitory action on A549 lung cancer cells.
{"title":"Synergistic Effects of Ethanol Extract of Allium sativum (Garlic) with DAPT and ATRA on Notch Signaling Targeted Molecular Action on Lung Cancer Cell line (A549)","authors":"Berlin Grace V M, R. Ravichandran, David Wilson D, S. Viswanathan, Siddikuzzaman, Lucia Bonati, R. Selvamani","doi":"10.2174/1570180820666230831095954","DOIUrl":"https://doi.org/10.2174/1570180820666230831095954","url":null,"abstract":"\u0000\u0000The activated oncogenic Notch signalling is an emerging target to treat cancer progression and recurrence. Synthetic inhibitors of Notch receptors are in pre-clinical studies. However, the overexpression of Notch signalling molecules at the gene level needs to be regulated to control cancer progression.\u0000\u0000\u0000\u0000We propose that this can be achieved by gene-regulatory drugs in combination with natural phytochemical compounds.\u0000\u0000\u0000\u0000The ethanol extract of Allium sativum alone and in combination with DAPT and ATRA were evaluated for cytotoxicity on A549 cells by MTT and Trypan blue assays. Their effects on Notch 1, Hes 1 and p53 gene expressions were studied by RT-PCR and qPCR. Their inhibition on metastatic invasion of A549 cells was analyzed by in vitro wound scratch assay. The phytochemicals of the extract were identified by GC-MS analysis.\u0000\u0000\u0000\u0000Many organosulfur compounds having anti-cancer potency were identified in GC-MS. The combination treatment with 50µg (IC50) of garlic extract exhibited a highly significant (P≤0.01) synergistic inhibitory effect on A549 cell growth and migration. It has also significantly reduced the expression of Notch 1 and Hes 1 oncogenes and enhanced p53 gene expression, compared with the individual treatments. This indicates the synergistic action of the extract on the downregulation of Notch signalling at the mRNA level.\u0000\u0000\u0000\u0000Our study results imply that the combination therapies have potent molecular treatment action via down-regulating Notch signaling target genes and upregulating p53 gene expression as an underlying mechanism of inhibitory action on A549 lung cancer cells.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86242819","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 : 2023-08-30DOI: 10.2174/1570180820666230830125155
Upendra Kumar, Rajnish Kumar, A. Mazumder, S. Salahuddin, Greesh Kumar
The fusion of two distinct and free pharmacologically active chemical moieties into single conjugate molecules can result in synergized pharmacological action of both moieties into the new composite molecule. Ultimately, it increases the therapeutic potentialof the newly formed hybrid compound which is more than the combination of each specific moiety’s therapeutic potential. So nowadays, it is common practice to combine at least two pharmacophores to create a particular compound with a powerful therapeutic effects. Quinoline has been reported with multiple pharmacological activities and industrial applications. On the other hand, hydrazones are also found very useful as herbicides, acaricides, rodenticides, insecticides, and various therapeutic applications. The conjugate containing quinoline and hydrazone is also being used as an anticancer, antibacterial, antifungal, antimalarial, anticonvulsant, anti-inflammatory, and antioxidant. The combination of two moieties yields a better therapeutic effect because of excellent efficacy and fewer side effects. Several synthetic methods have been employed in recent times to synthesize quinoline-hydrazone conjugates which are listed in the manuscript with their merits and demerits. The structure-activity relationship relating to their pharmacological actions with molecular structure has also been highlighted. The article aims to provide a good toolkit and comprehension to the medicinal chemists, for their future work, comprising of quinoline-hydrazone hybrid compounds.
{"title":"Quinoline-Hydrazone Conjugates:Recent Insights into Synthetic Strategies, Structure-Activity Relationship, and Biological Activities","authors":"Upendra Kumar, Rajnish Kumar, A. Mazumder, S. Salahuddin, Greesh Kumar","doi":"10.2174/1570180820666230830125155","DOIUrl":"https://doi.org/10.2174/1570180820666230830125155","url":null,"abstract":"\u0000\u0000The fusion of two distinct and free pharmacologically active chemical moieties into single conjugate molecules can result in synergized pharmacological action of both moieties into the new composite molecule. Ultimately, it increases the therapeutic potentialof the newly formed hybrid compound which is more than the combination of each specific moiety’s therapeutic potential. So nowadays, it is common practice to combine at least two pharmacophores to create a particular compound with a powerful therapeutic effects. Quinoline has been reported with multiple pharmacological activities and industrial applications. On the other hand, hydrazones are also found very useful as herbicides, acaricides, rodenticides, insecticides, and various therapeutic applications. The conjugate containing quinoline and hydrazone is also being used as an anticancer, antibacterial, antifungal, antimalarial, anticonvulsant, anti-inflammatory, and antioxidant. The combination of two moieties yields a better therapeutic effect because of excellent efficacy and fewer side effects. Several synthetic methods have been employed in recent times to synthesize quinoline-hydrazone conjugates which are listed in the manuscript with their merits and demerits. The structure-activity relationship relating to their pharmacological actions with molecular structure has also been highlighted. The article aims to provide a good toolkit and comprehension to the medicinal chemists, for their future work, comprising of quinoline-hydrazone hybrid compounds.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76444081","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 : 2023-08-29DOI: 10.2174/1570180820666230829093322
P. Tiber, Sera Averbek, S. Sevinç, Olca Kilinç, P. Süzgün, Ş. Küçükgüzel, O. Orun
Nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used for their anti-inflammatory and analgesic properties, have also been found to prevent cancer. (±)(R,S) Etodolac is an NSAID that belongs to the class of cyclooxygenase-2 inhibitors. Various derivatives of etodolac are synthesized to boost its anti-proliferative action and lessen its potential negative effects. In our earlier studies, some novel derivatives of etodolac exhibited stronger cytotoxic effects on prostate cell lines and had similar effects on leukemia cells in pre-screening experiments. Using the K562 leukemia cell line as a model, we sought to investigate the anti-cancer properties of a hydrazide-hydrozone derivative (SGK-205) and a 4-thiazolidinone derivative of etodolac (SGK-216). In the current investigation, SGK-205 and SGK-216 compounds were administered to K562 cells for 24 and 48 hours at concentrations of 10, 25, 50, 75 and 100 μM. Cell viability was assessed using the MTT test, and apoptosis by Annexin V-PI staining and mitochondrial membrane potential assays, together with mRNA expressions of apoptotic proteins. The levels of the proteins, HER2 and COX2, were also examined to evaluate COX2 inhibitory capacity. In K562 cells, there was a definite dose-dependent response to SGK-205 and SGK-216 compounds. Results from MTT viability tests, together with mitochondrial membrane potential measurements and Annexin V-PI staining, revealed that SGK-216 and SGK-205 significantly outperformed etodolac in terms of their apoptotic and anti-proliferative activities. The concentration range of 10-20 M for both chemicals was sufficient to start biological responses. Apoptosis was also investigated through the expressions of pro- and anti-apoptotic proteins. Additionally, gene expression research demonstrated SGK-205 to be a beneficial substitute to etodolac in lowering COX-2 and human epidermal growth factor receptor-2 (HER2) expression. Our data indicated both derivatives to have higher anti-proliferative and apoptotic effects compared to etodolac. An overall assessment highlighting apoptotic induction potential, acceptable toxicity levels, a consistent dose-response relationship, and COX2 inhibitory actions, in particular, indicated SGK-205 as a viable novel therapeutic.
{"title":"Evaluation of Hydrazide-hydrazone and 4-thiazolidinone Derivatives of Etodolac as Potential Anticancer Agents in Leukemia Cells","authors":"P. Tiber, Sera Averbek, S. Sevinç, Olca Kilinç, P. Süzgün, Ş. Küçükgüzel, O. Orun","doi":"10.2174/1570180820666230829093322","DOIUrl":"https://doi.org/10.2174/1570180820666230829093322","url":null,"abstract":"\u0000\u0000Nonsteroidal anti-inflammatory drugs (NSAIDs), which are commonly used for their anti-inflammatory and analgesic properties, have also been found to prevent cancer. (±)(R,S) Etodolac is an NSAID that belongs to the class of cyclooxygenase-2 inhibitors. Various derivatives of etodolac are synthesized to boost its anti-proliferative action and lessen its potential negative effects. In our earlier studies, some novel derivatives of etodolac exhibited stronger cytotoxic effects on prostate cell lines and had similar effects on leukemia cells in pre-screening experiments.\u0000\u0000\u0000\u0000Using the K562 leukemia cell line as a model, we sought to investigate the anti-cancer properties of a hydrazide-hydrozone derivative (SGK-205) and a 4-thiazolidinone derivative of etodolac (SGK-216).\u0000\u0000\u0000\u0000In the current investigation, SGK-205 and SGK-216 compounds were administered to K562 cells for 24 and 48 hours at concentrations of 10, 25, 50, 75 and 100 μM. Cell viability was assessed using the MTT test, and apoptosis by Annexin V-PI staining and mitochondrial membrane potential assays, together with mRNA expressions of apoptotic proteins. The levels of the proteins, HER2 and COX2, were also examined to evaluate COX2 inhibitory capacity.\u0000\u0000\u0000\u0000In K562 cells, there was a definite dose-dependent response to SGK-205 and SGK-216 compounds. Results from MTT viability tests, together with mitochondrial membrane potential measurements and Annexin V-PI staining, revealed that SGK-216 and SGK-205 significantly outperformed etodolac in terms of their apoptotic and anti-proliferative activities. The concentration range of 10-20 M for both chemicals was sufficient to start biological responses. Apoptosis was also investigated through the expressions of pro- and anti-apoptotic proteins. Additionally, gene expression research demonstrated SGK-205 to be a beneficial substitute to etodolac in lowering COX-2 and human epidermal growth factor receptor-2 (HER2) expression.\u0000\u0000\u0000\u0000Our data indicated both derivatives to have higher anti-proliferative and apoptotic effects compared to etodolac. An overall assessment highlighting apoptotic induction potential, acceptable toxicity levels, a consistent dose-response relationship, and COX2 inhibitory actions, in particular, indicated SGK-205 as a viable novel therapeutic.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79841723","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 : 2023-08-29DOI: 10.2174/1570180820666230829105308
XiaoDie Chen, YuanZe Shi, Na Yu, Jiali Li, Jinping Wu, Xuemin Zhao, M. Shu, Zhihua Lin
WD repeat structural domain 5 (WDR5), which plays an important role in various biological functions through epigenetic regulation, is aberrantly expressed in human cancers, and is an effective target for the discovery of anticancer drugs. In this paper, QSAR modeling analysis, including comparative molecular field (CoMFA) and comparative molecular similarity index analysis field (CoMSIA), was first performed using 41 pyrroloimidazole analogs. The results showed q2=0.667 and r2=0.981 in CoMFA and q2=0.662 and r2=0.983 in CoMSIA. Molecular docking and molecular dynamics simulations further confirmed the interaction and binding affinity of the inhibitors with key residues of the proteins, for example, PHE149, PHE133, and CYS261. Based on QSAR and docking studies, seven new compounds with high scores and qualified ADMET performance were designed. In this study, new ideas have been provided for exploring new WDR5 inhibitors.
{"title":"Identification of Pyrroloimidazoles as Potential Inhibitors of WDR5-WIN-Site by 3D-QSAR Molecular Simulation","authors":"XiaoDie Chen, YuanZe Shi, Na Yu, Jiali Li, Jinping Wu, Xuemin Zhao, M. Shu, Zhihua Lin","doi":"10.2174/1570180820666230829105308","DOIUrl":"https://doi.org/10.2174/1570180820666230829105308","url":null,"abstract":"\u0000\u0000WD repeat structural domain 5 (WDR5), which plays an important role in various biological functions through epigenetic regulation, is aberrantly expressed in human cancers, and is an effective target for the discovery of anticancer drugs.\u0000\u0000\u0000\u0000In this paper, QSAR modeling analysis, including comparative molecular field (CoMFA) and comparative molecular similarity index analysis field (CoMSIA), was first performed using 41 pyrroloimidazole analogs. The results showed q2=0.667 and r2=0.981 in CoMFA and q2=0.662 and r2=0.983 in CoMSIA. Molecular docking and molecular dynamics simulations further confirmed the interaction and binding affinity of the inhibitors with key residues of the proteins, for example, PHE149, PHE133, and CYS261.\u0000\u0000\u0000\u0000Based on QSAR and docking studies, seven new compounds with high scores and qualified ADMET performance were designed.\u0000\u0000\u0000\u0000In this study, new ideas have been provided for exploring new WDR5 inhibitors.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87172698","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}
Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease. Shugan Jiangzhi Decoction (SJD), a traditional Chinese medicine (TCM) formula which consists of six Chinese herbs, has been used for treating hyperlipidemia, obesity, and fatty liver in Guangdong Provincial Hospital of Traditional Chinese Medicine for over twenty years. This study aims to elucidate the chemical basis and the molecular mechanism of SJD against NAFLD. The main components of SJD were determined by High Performance Liquid Chromatography (HPLC). Then the high-fat diet (HFD)-induced NAFLD rat model was established. After treatment with different doses of SJD, the body weight of rats was measured weekly. On the last day of the experiments, the hepatic morphology, histopathology changes, and the serum lipid levels were detected. Then techniques of network pharmacology were employed to predict the anti-NAFLD mechanism of SJD. At last, the expression levels of proteins were measured by western blot to verify the mechanism. Nine chemical constituents of SJD were identified from HPLC fingerprint spectrum. For the in vivo experiment, NAFLD rat model was constructed successfully by feeding high-fat diet (HFD) for 8 weeks. The following treatment with SJD for 6 weeks decreased the fatty droplet accumulation in the liver obviously. Meanwhile, the serum level of high-density lipoprotein cholesterol (HDL-c) was increased, while the levels of low-density lipoprotein cholesterol (LDL-c), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were decreased after SJD treatment(p<0.05). The results of network pharmacology indicated that SJD might improve NAFLD via regulating the AMPK/PPAR signaling pathway. Then, the western blot assay confirmed that SJD activated the AMPK/PPAR signaling pathway in the liver of rats. SJD improves HFD-induced NAFLD in rats via AMPK/PPAR signaling pathway. Thus, our study suggests that SJD can serve as a therapeutic agent for the prevention and treatment of NAFLD.
{"title":"Shugan Jiangzhi Decoction Alleviates Nonalcoholic Fatty Liver Disease（NAFLD） via Regulating AMPK/PPAR Signaling Pathway","authors":"Dinghong Wu, Lijuan Chen, Wen Li, Yanli Fu, Yuhe Lei, Wenjian Xie, Suihua Rong, Ning Li, Miaomiao Zhang, Jiayi He, Yuanchun Chen","doi":"10.2174/1570180820666230828125057","DOIUrl":"https://doi.org/10.2174/1570180820666230828125057","url":null,"abstract":"\u0000\u0000Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disease. Shugan Jiangzhi Decoction (SJD), a traditional Chinese medicine (TCM) formula which consists of six Chinese herbs, has been used for treating hyperlipidemia, obesity, and fatty liver in Guangdong Provincial Hospital of Traditional Chinese Medicine for over twenty years.\u0000\u0000\u0000\u0000This study aims to elucidate the chemical basis and the molecular mechanism of SJD against NAFLD.\u0000\u0000\u0000\u0000The main components of SJD were determined by High Performance Liquid Chromatography (HPLC). Then the high-fat diet (HFD)-induced NAFLD rat model was established. After treatment with different doses of SJD, the body weight of rats was measured weekly. On the last day of the experiments, the hepatic morphology, histopathology changes, and the serum lipid levels were detected. Then techniques of network pharmacology were employed to predict the anti-NAFLD mechanism of SJD. At last, the expression levels of proteins were measured by western blot to verify the mechanism.\u0000\u0000\u0000\u0000Nine chemical constituents of SJD were identified from HPLC fingerprint spectrum. For the in vivo experiment, NAFLD rat model was constructed successfully by feeding high-fat diet (HFD) for 8 weeks. The following treatment with SJD for 6 weeks decreased the fatty droplet accumulation in the liver obviously. Meanwhile, the serum level of high-density lipoprotein cholesterol (HDL-c) was increased, while the levels of low-density lipoprotein cholesterol (LDL-c), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were decreased after SJD treatment(p<0.05). The results of network pharmacology indicated that SJD might improve NAFLD via regulating the AMPK/PPAR signaling pathway. Then, the western blot assay confirmed that SJD activated the AMPK/PPAR signaling pathway in the liver of rats.\u0000\u0000\u0000\u0000SJD improves HFD-induced NAFLD in rats via AMPK/PPAR signaling pathway. Thus, our study suggests that SJD can serve as a therapeutic agent for the prevention and treatment of NAFLD.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88943390","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 : 2023-08-28DOI: 10.2174/1570180820666230828151523
P. Singh, Satish Bhoge, Deepak Das, Yakub M. Ali, Abhijeet S Dhulap
Inflammation is the first response and an alarming signal for the onset of chronic disease. Most of the anti-inflammatory drugs available in the market are reported to have undesirable gastrointestinal toxicities. Therefore, it is of urgent significance to develop anti-inflammatory drugs with low toxicity and good efficacy. We created a targeted scaffold based on a literature review by combining the different structural characteristics of furan and benzyl amides into a single pharmacophore. A series of eighteen furan-based derivatives (1-18) were designed, synthesized for in-vitro and in-vivo anti-inflammatory activity. The characterization of synthesized compounds was elucidated by techniques like 1H-NMR, 13C-NMR, FT-IR and MS. The synthetic compounds were examined through molecular docking studies on TNF-α for probable binding mode and interactions with hydrophilic and hydrophobic pocket of TNF-α in comparison to standard drug (Indomethacin). When compared to the standard treatment, compounds 18, 15 and 9 displayed a remarkable inhibitory effect on the production of TNF-α and in-vivo inflammatory activity with no damage to stomach and reduction of LPO. The compounds 18, 15 and 9 might be a good consideration for potential anti-inflammatory agents.
{"title":"Design, Synthesis, Anti-inflammatory Evaluation and in silico Molecular Docking of Novel Furan-based Derivatives as Potential TNF-α Production Inhibitors","authors":"P. Singh, Satish Bhoge, Deepak Das, Yakub M. Ali, Abhijeet S Dhulap","doi":"10.2174/1570180820666230828151523","DOIUrl":"https://doi.org/10.2174/1570180820666230828151523","url":null,"abstract":"\u0000\u0000Inflammation is the first response and an alarming signal for the onset of chronic disease. Most of the anti-inflammatory drugs available in the market are reported to have undesirable gastrointestinal toxicities. Therefore, it is of urgent significance to develop anti-inflammatory drugs with low toxicity and good efficacy.\u0000\u0000\u0000\u0000We created a targeted scaffold based on a literature review by combining the different structural characteristics of furan and benzyl amides into a single pharmacophore. A series of eighteen furan-based derivatives (1-18) were designed, synthesized for in-vitro and in-vivo anti-inflammatory activity. The characterization of synthesized compounds was elucidated by techniques like 1H-NMR, 13C-NMR, FT-IR and MS.\u0000\u0000\u0000\u0000The synthetic compounds were examined through molecular docking studies on TNF-α for probable binding mode and interactions with hydrophilic and hydrophobic pocket of TNF-α in comparison to standard drug (Indomethacin).\u0000\u0000\u0000\u0000When compared to the standard treatment, compounds 18, 15 and 9 displayed a remarkable inhibitory effect on the production of TNF-α and in-vivo inflammatory activity with no damage to stomach and reduction of LPO. The compounds 18, 15 and 9 might be a good consideration for potential anti-inflammatory agents.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76222680","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 : 2023-08-25DOI: 10.2174/1570180820666230825103609
M. N Noolvi, Parin Salim Sidat, Sanket Rathod, Rahul Patil, Prafulla Choudhari3, R. Wagh, V. Beldar
Cancer is a group of diseases distinguished by uncontrollable cell division. The underlying causes are complex and include multiple genes and pathways. Many targeted therapies are effective in treating cancer. In Current research, we were using the autophagy pathway of cell death. Here, we are exploring some thiadiazole derivatives that are specific to ULK inhibition, and for a better understanding of ligand and target we have assessed all the molecules by using some computational approaches. The current study focuses on the In-silico evaluation and molecular prediction of some thiadiazole derivatives as ULK (Human Autophagy Initiating Kinase) inhibitors. Some thiadiazole derivatives were subjected to In-silico evaluation involving Molecular docking, Pharmacophore modelling, PASS prediction and Molecular dynamic simulation (MD) along with PCA analysis. In addition, drug-likeness was determined using the Lipinski rule of five. Among all proposed thiadiazole derivatives, we found a few ligands such as 2d, 4e, and 4d with the lowest binding energy score (-11.3 kcal/mol, -11.2 kcal/mol and -11.0 kcal/mol), respectively. Drug-likeness properties include an excellent lipophilic character with good permeability (1.97, 2.86, and 2.73) observed with the above derivatives. In addition, better binding specificity (94.79, 94.70, and 74.57) and better enzyme potential inhibitory activity (0.04, 0.00, 0.14) were noticed with ULK receptors in comparison to STD (Standard) molecules. Using pharmacophore modelling, we identified potential chemical features of the designed compounds. Moreover, molecular dynamics and PCA analysis of compound 4d showed stable conformation with 4WNP. Compared to STD compounds, with no violation, the bioactivity and likeness score of ligands 2d, 4e, and 4d were relatively high, indicating that they were excellent ULK inhibitors. These ligands also had the lowest binding score, which may aid in determining the stability of ligands. Pharmacophore modeling data suggested the essential chemical features of designed compounds required for the activity. The MD simulation and PCA study confirmed the stability of the 4d complex with 4WNP. These parameters allow consideration of the most promising candidates to be synthesized.
{"title":"Exploration of Virtually Designed and Developed Thiadiazole Derivatives as ULK1/2 Inhibitors: In silico Approach","authors":"M. N Noolvi, Parin Salim Sidat, Sanket Rathod, Rahul Patil, Prafulla Choudhari3, R. Wagh, V. Beldar","doi":"10.2174/1570180820666230825103609","DOIUrl":"https://doi.org/10.2174/1570180820666230825103609","url":null,"abstract":"\u0000\u0000Cancer is a group of diseases distinguished by uncontrollable cell division. The underlying causes are complex and include multiple genes and pathways. Many targeted therapies are effective in treating cancer. In Current research, we were using the autophagy pathway of cell death. Here, we are exploring some thiadiazole derivatives that are specific to ULK inhibition, and for a better understanding of ligand and target we have assessed all the molecules by using some computational approaches.\u0000\u0000\u0000\u0000The current study focuses on the In-silico evaluation and molecular prediction of some thiadiazole derivatives as ULK (Human Autophagy Initiating Kinase) inhibitors.\u0000\u0000\u0000\u0000Some thiadiazole derivatives were subjected to In-silico evaluation involving Molecular docking, Pharmacophore modelling, PASS prediction and Molecular dynamic simulation (MD) along with PCA analysis. In addition, drug-likeness was determined using the Lipinski rule of five.\u0000\u0000\u0000\u0000Among all proposed thiadiazole derivatives, we found a few ligands such as 2d, 4e, and 4d with the lowest binding energy score (-11.3 kcal/mol, -11.2 kcal/mol and -11.0 kcal/mol), respectively. Drug-likeness properties include an excellent lipophilic character with good permeability (1.97, 2.86, and 2.73) observed with the above derivatives. In addition, better binding specificity (94.79, 94.70, and 74.57) and better enzyme potential inhibitory activity (0.04, 0.00, 0.14) were noticed with ULK receptors in comparison to STD (Standard) molecules. Using pharmacophore modelling, we identified potential chemical features of the designed compounds. Moreover, molecular dynamics and PCA analysis of compound 4d showed stable conformation with 4WNP.\u0000\u0000\u0000\u0000Compared to STD compounds, with no violation, the bioactivity and likeness score of ligands 2d, 4e, and 4d were relatively high, indicating that they were excellent ULK inhibitors. These ligands also had the lowest binding score, which may aid in determining the stability of ligands. Pharmacophore modeling data suggested the essential chemical features of designed compounds required for the activity. The MD simulation and PCA study confirmed the stability of the 4d complex with 4WNP. These parameters allow consideration of the most promising candidates to be synthesized.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88889958","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 : 2023-08-25DOI: 10.2174/1570180820666230825122908
R. Haloui, Khaoula Mkhayar, O. Daoui, Y. Rhazi, Kaouakeb Elkhattabi, M. E. Yazidi, Samir Chtita, Amal Haoudi, S. Elkhattabi
Cancer is one of the most serious diseases affecting human health. It has been considered by the World Health Organization (WHO) as one of the main causes of death in the world. For this reason, a set of benzofuran derivatives are studied in silico using the 3D-QSAR, drug-likeness, ADMET properties, and molecular docking The 3D-QSAR study was performed using CoMFA and CoMSIA techniques to generate two reliable 3D-QSAR models and effectively predict the biological activity of new molecules in an efficient manner. The reliability and efficacy of the developed models were validated by the Y-randomisation test internal and external validation. Based on the interesting information obtained from the CoMFA and CoMSIA contour maps, we designed five new moleculesT1-T5. The lysine-specific demethylase 1 (LSD1) inhibitory activities of the newly designed molecules were predicted in silico, and their obtained results show that these molecules have a higher inhibitory activity of LSD1 than the most active synthesized molecule N4. The five designed LSD1 inhibitors were subjected to the drug-likeness and ADMET properties test. The results of this test show that two molecules T4 and T5 are non-toxic and have good pharmacokinetic properties compared to the synthesized molecule N4. The two molecules T4 and T5 chosen for their ADMET properties were analyzed by molecular docking simulation. The obtained results show the two molecules T4 and T5 are more localized and stable in the LSD1 pocket than the molecules N4 The newly designed molecules T4 and T5 were proposed as the best candidates to obtain a better inhibition of LSD1 compared to the synthesized molecule N4. Finally, we have proposed synthetic pathways for the designed molecules.
{"title":"Computational Study on Benzofuran Derivatives as Potent Lysine-Specific Demethylase 1 Inhibitors using 3D QSAR, ADMET Prediction, and Molecular Docking","authors":"R. Haloui, Khaoula Mkhayar, O. Daoui, Y. Rhazi, Kaouakeb Elkhattabi, M. E. Yazidi, Samir Chtita, Amal Haoudi, S. Elkhattabi","doi":"10.2174/1570180820666230825122908","DOIUrl":"https://doi.org/10.2174/1570180820666230825122908","url":null,"abstract":"\u0000\u0000Cancer is one of the most serious diseases affecting human health. It has been considered by the World Health Organization (WHO) as one of the main causes of death in the world. For this reason, a set of benzofuran derivatives are studied in silico using the 3D-QSAR, drug-likeness, ADMET properties, and molecular docking\u0000\u0000\u0000\u0000The 3D-QSAR study was performed using CoMFA and CoMSIA techniques to generate two reliable 3D-QSAR models and effectively predict the biological activity of new molecules in an efficient manner. The reliability and efficacy of the developed models were validated by the Y-randomisation test internal and external validation. Based on the interesting information obtained from the CoMFA and CoMSIA contour maps, we designed five new moleculesT1-T5. The lysine-specific demethylase 1 (LSD1) inhibitory activities of the newly designed molecules were predicted in silico, and their obtained results show that these molecules have a higher inhibitory activity of LSD1 than the most active synthesized molecule N4. The five designed LSD1 inhibitors were subjected to the drug-likeness and ADMET properties test.\u0000\u0000\u0000\u0000The results of this test show that two molecules T4 and T5 are non-toxic and have good pharmacokinetic properties compared to the synthesized molecule N4. The two molecules T4 and T5 chosen for their ADMET properties were analyzed by molecular docking simulation. The obtained results show the two molecules T4 and T5 are more localized and stable in the LSD1 pocket than the molecules N4\u0000\u0000\u0000\u0000The newly designed molecules T4 and T5 were proposed as the best candidates to obtain a better inhibition of LSD1 compared to the synthesized molecule N4. Finally, we have proposed synthetic pathways for the designed molecules.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76013667","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 : 2023-08-23DOI: 10.2174/1570180820666230823091640
Fereshteh Asgharzadeh, S. Nazari, Hamideh Naeimi, F. Rahmani, A. Avan, M. Khazaei, S. Hassanian
This study aimed to investigate the protective effects of phytosomal curcumin and/or shilajit in reducing post-surgical tendon adhesion band formation in a rat model. Tendon adhesion is one of the severe complications after tendon surgery which causes limited tendon movement and functional disability. According to the central role of inflammatory reactions in fibrosis and the formation of tendon adhesions, we investigated the therapeutic effects of phytosomal curcumin and shilajit either alone or in combination on reducing post-surgical tendon adhesion band formation in a rat model. We randomly divided 36 Wistar male rats into six equal groups. (A) Control group with no surgical incision and no intervention. (B) Sham group with surgical incision, but no adhesion, (C) Positive control group with total surgical transection and adhesion receiving normal saline daily, (D-F) Treatment groups which are the same as group C except that rats were treated with the following drugs. Phytosomal curcumin alone (250 µL/day; orally), shilajit alone (500 mg/kg/day; orally) and a combination of phytosomal curcumin + shilajit. In groups with surgical intervention, the rats' Achilles tendons were cut and repaired with a modified Kessler technique. At 3 weeks, all rats were euthanized. Histological and pathological scoring systems were used to evaluate the protective effects of phytosomal curcumin and/or shilajit in reducing adhesion bands at the site of tendon injuries. Our results revealed that the administration of phytosomal curcumin and/or shilajit remarkably reduced length, density, grading, severity, and thickness of post-surgical adhesion bands. Compared to the untreated control group, the histological changes and inflammatory reactions were significantly attenuated in treated rats. Furthermore, treatment with phytosomal curcumin and/or shilajit inhibited fibrotic responses by alleviating collagen deposition, fibrosis quantity, fibrosis grading, and total fibrosis scores, as visualized by Masson’s trichrome staining. Our findings indicated the anti-inflammatory and anti-fibrotic properties of phytosomal curcumin and/or shilajit supporting their therapeutic potential in preventing post-operative tendon adhesion bands.
{"title":"Phytosomal curcumin and shilajit decrease adhesion bands post-Achilles tendon surgery in animal model","authors":"Fereshteh Asgharzadeh, S. Nazari, Hamideh Naeimi, F. Rahmani, A. Avan, M. Khazaei, S. Hassanian","doi":"10.2174/1570180820666230823091640","DOIUrl":"https://doi.org/10.2174/1570180820666230823091640","url":null,"abstract":"\u0000\u0000This study aimed to investigate the protective effects of phytosomal curcumin and/or shilajit in reducing post-surgical tendon adhesion band formation in a rat model.\u0000\u0000\u0000\u0000Tendon adhesion is one of the severe complications after tendon surgery which causes limited tendon movement and functional disability.\u0000\u0000\u0000\u0000According to the central role of inflammatory reactions in fibrosis and the formation of tendon adhesions, we investigated the therapeutic effects of phytosomal curcumin and shilajit either alone or in combination on reducing post-surgical tendon adhesion band formation in a rat model.\u0000\u0000\u0000\u0000We randomly divided 36 Wistar male rats into six equal groups. (A) Control group with no surgical incision and no intervention. (B) Sham group with surgical incision, but no adhesion, (C) Positive control group with total surgical transection and adhesion receiving normal saline daily, (D-F) Treatment groups which are the same as group C except that rats were treated with the following drugs. Phytosomal curcumin alone (250 µL/day; orally), shilajit alone (500 mg/kg/day; orally) and a combination of phytosomal curcumin + shilajit. In groups with surgical intervention, the rats' Achilles tendons were cut and repaired with a modified Kessler technique. At 3 weeks, all rats were euthanized. Histological and pathological scoring systems were used to evaluate the protective effects of phytosomal curcumin and/or shilajit in reducing adhesion bands at the site of tendon injuries.\u0000\u0000\u0000\u0000Our results revealed that the administration of phytosomal curcumin and/or shilajit remarkably reduced length, density, grading, severity, and thickness of post-surgical adhesion bands. Compared to the untreated control group, the histological changes and inflammatory reactions were significantly attenuated in treated rats. Furthermore, treatment with phytosomal curcumin and/or shilajit inhibited fibrotic responses by alleviating collagen deposition, fibrosis quantity, fibrosis grading, and total fibrosis scores, as visualized by Masson’s trichrome staining.\u0000\u0000\u0000\u0000Our findings indicated the anti-inflammatory and anti-fibrotic properties of phytosomal curcumin and/or shilajit supporting their therapeutic potential in preventing post-operative tendon adhesion bands.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88480692","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 : 2023-08-23DOI: 10.2174/1570180820666230823093545
Jiawen Deng, Si Zhang, Yan Tan, Jing Zou, Meiling Liu, Zehua Yang, X. Yao, Pengbing Mi, Xing Zheng
Ursolic acid (UA) is a widely distributed triterpenoid in nature. Due to its easy availability and multiple pharmacological activities, ursolic acid has attracted much attention in the field of medicine and pharmacology. To overcome the disadvantages of bioavailability and poor water solubility during the ursolic acid application, we focused on the synthetic and medicinal properties of UA derivatives modified at C-3 and C-28 sites. This review presents the synthesis of UA derivatives with modification at C-3 and C-28 sites and their pharmacological activity, which may provide some important information for further research and development of UA-based drugs.
{"title":"The Synthesis and Pharmacological Activity of Ursolic Acid Derivatives Modified at C-28 and C-3 Sites.","authors":"Jiawen Deng, Si Zhang, Yan Tan, Jing Zou, Meiling Liu, Zehua Yang, X. Yao, Pengbing Mi, Xing Zheng","doi":"10.2174/1570180820666230823093545","DOIUrl":"https://doi.org/10.2174/1570180820666230823093545","url":null,"abstract":"\u0000\u0000Ursolic acid (UA) is a widely distributed triterpenoid in nature. Due to its easy availability and multiple pharmacological activities, ursolic acid has attracted much attention in the field of medicine and pharmacology.\u0000\u0000\u0000\u0000To overcome the disadvantages of bioavailability and poor water solubility during the ursolic acid application, we focused on the synthetic and medicinal properties of UA derivatives modified at C-3 and C-28 sites.\u0000\u0000\u0000\u0000This review presents the synthesis of UA derivatives with modification at C-3 and C-28 sites and their pharmacological activity, which may provide some important information for further research and development of UA-based drugs.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89455018","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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