Background: Severe acute respiratory syndrome coronavirus 2 main protease (SARSCoV- 2 Mpro) has been shown to be an effective target for inhibiting novel coronaviruses, which can be used as a crucial breakthrough for developing drugs to treat the coronavirus disease 2019 (COVID-19). Methods: To design novel SARS-CoV-2 Mpro inhibitors, we conducted 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation on 64 quinazolin-4-one derivatives. Results: Comparative molecular field analysis (CoMFA) model (q2 = 0.590, R2 = 0.962), comparative molecular similarity index analysis (CoMSIA) model (q2 = 0.628, R2 = 0.923), and external validation indicated that the stability, reliability, and prediction performance of our constructed model were excellent. We designed 8 inhibitors with stronger antiviral activities through the three-dimensional equipotential field. Molecular docking and MD simulation probed the interactions of compounds and SARS-CoV-2 Mpro. This indicated that amino acid residues, including Met165, Met49, and Cys145, were very important in combination with the compounds. The prediction results of ADME/T and Lipinski’s rule of five indicated that the new compounds had favorable drug-like and pharmacokinetic properties. Conclusion: This study provides new ideas for exploring new drugs against COVID-19
{"title":"Structural Optimization of Quinazolin-4-One Derivatives as Novel SARS-CoV-2 Mpro Inhibitors by Molecular Simulation","authors":"Jinping Wu, Peng Li, Yucheng Mu, Ruiguang Peng, Zhongyao Zhao, Jinke Lei, Aiping Tu, Zhiting Gao, Yixiao Bai, Gang Wu","doi":"10.2174/0115701808330125240812104856","DOIUrl":"https://doi.org/10.2174/0115701808330125240812104856","url":null,"abstract":"Background: Severe acute respiratory syndrome coronavirus 2 main protease (SARSCoV- 2 Mpro) has been shown to be an effective target for inhibiting novel coronaviruses, which can be used as a crucial breakthrough for developing drugs to treat the coronavirus disease 2019 (COVID-19). Methods: To design novel SARS-CoV-2 Mpro inhibitors, we conducted 3D-QSAR, molecular docking, and molecular dynamics (MD) simulation on 64 quinazolin-4-one derivatives. Results: Comparative molecular field analysis (CoMFA) model (q2 = 0.590, R2 = 0.962), comparative molecular similarity index analysis (CoMSIA) model (q2 = 0.628, R2 = 0.923), and external validation indicated that the stability, reliability, and prediction performance of our constructed model were excellent. We designed 8 inhibitors with stronger antiviral activities through the three-dimensional equipotential field. Molecular docking and MD simulation probed the interactions of compounds and SARS-CoV-2 Mpro. This indicated that amino acid residues, including Met165, Met49, and Cys145, were very important in combination with the compounds. The prediction results of ADME/T and Lipinski’s rule of five indicated that the new compounds had favorable drug-like and pharmacokinetic properties. Conclusion: This study provides new ideas for exploring new drugs against COVID-19","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192106","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 : 2024-08-29DOI: 10.2174/0115701808334616240822055800
Mohammed Naveez Valathoor, Subhashree Venugopal
Background and Objectives:: Salmonella typhimurium is a foodborne pathogen that is a major concern for global health. Flagellin (FliC) is an essential protein in Salmonella typhimurium for both motility and virulence and is a key component of flagella. Hence, focusing on FliC protein is a promising strategy for developing new anti-Salmonella agents. Colchicum luteum, a medicinal plant, shows promising antimicrobial properties. Thus, this study explores the therapeutic potential of Colchicum luteum against FliC protein using computational methods in comparison to the standard antibiotic ciprofloxacin. Methods: Molecular docking simulation was performed to evaluate the binding affinity and interaction pattern of bioactive compounds present in Colchicum luteum and ciprofloxacin against FliC protein. This study also analysed protein stability and dynamics studies of the apoprotein, ciprofloxacin, kesselringine, and gloriosine complexes using molecular dynamic (MD) simulation. The MMGBSA method computed binding free energies Results: Through docking simulations, it was found that gloriosine and kesselringine have strong binding affinity with FliC protein, similar to ciprofloxacin. MD simulation showed consistent protein- ligand complexes during the entire simulation. The MMGBSA analysis confirmed the positive interactions observed in the docking results, showing binding free energies similar to ciprofloxacin. Conclusion: This study suggests that the phytocompound of Colchicum luteum shows promise as a source for creating anti-Salmonella typhimurium agents that target FliC protein. These results suggest that Colchicum luteum may have therapeutic potential against Salmonella typhimurium infections and should be further studied through in vitro and in vivo experiments.
{"title":"Therapeutic Potential of Colchicum luteum Against Flagellin (FliC) in Salmonella typhimurium: An In silico Approach","authors":"Mohammed Naveez Valathoor, Subhashree Venugopal","doi":"10.2174/0115701808334616240822055800","DOIUrl":"https://doi.org/10.2174/0115701808334616240822055800","url":null,"abstract":"Background and Objectives:: Salmonella typhimurium is a foodborne pathogen that is a major concern for global health. Flagellin (FliC) is an essential protein in Salmonella typhimurium for both motility and virulence and is a key component of flagella. Hence, focusing on FliC protein is a promising strategy for developing new anti-Salmonella agents. Colchicum luteum, a medicinal plant, shows promising antimicrobial properties. Thus, this study explores the therapeutic potential of Colchicum luteum against FliC protein using computational methods in comparison to the standard antibiotic ciprofloxacin. Methods: Molecular docking simulation was performed to evaluate the binding affinity and interaction pattern of bioactive compounds present in Colchicum luteum and ciprofloxacin against FliC protein. This study also analysed protein stability and dynamics studies of the apoprotein, ciprofloxacin, kesselringine, and gloriosine complexes using molecular dynamic (MD) simulation. The MMGBSA method computed binding free energies Results: Through docking simulations, it was found that gloriosine and kesselringine have strong binding affinity with FliC protein, similar to ciprofloxacin. MD simulation showed consistent protein- ligand complexes during the entire simulation. The MMGBSA analysis confirmed the positive interactions observed in the docking results, showing binding free energies similar to ciprofloxacin. Conclusion: This study suggests that the phytocompound of Colchicum luteum shows promise as a source for creating anti-Salmonella typhimurium agents that target FliC protein. These results suggest that Colchicum luteum may have therapeutic potential against Salmonella typhimurium infections and should be further studied through in vitro and in vivo experiments.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192107","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: Intra-abdominal adhesions are a commonly occurring postoperative complication following abdominopelvic surgery. Peritoneal adhesion formation can lead to infertility, chronic pelvic pain, and intestinal obstruction. The anti-inflammatory and anti-oxidant activities of Ganoderma lucidum Karst (G. lucidum) and Ziziphus jujuba Mill (Z. jujuba) have been reported. Here, we have explored the therapeutic potential of Ganoderma lucidum Karst (G. lucidum) and Z. jujuba against postsurgical adhesion band formation. The NC3Rs ARRIVE guidelines were followed during experimental studies. Methods: G. lucidum powder (800 mg/kg) and Z. jujuba powder (400 mg/kg) were administered using oral gavage to different groups of male albino Wistar rats. After ten days of treatment, macroscopic evidence for peritoneal adhesions and adhesion band score were determined. Furthermore, the anti-inflammatory and antifibrosis effects of G. lucidum and Z. jujuba were assessed using histopathology, ELISA, and real-time polymerase chain reaction methods. Also, alterations in some oxidative stress parameters were evaluated. Results: G. lucidum and Z. jujuba significantly decreased adhesion bands and were associated with a reduction in inflammatory cell infiltration into damaged tissues and the mRNA and protein expression of inflammatory cytokines via modulation of TNF-α, IL-6, IL-1β, and TGF-β. Moreover, both agents inhibited fibrotic adhesion band formation by decreasing collagen deposition and reducing profibrotic marker expression, Col1A1, at the peritoneum adhesion tissues. G. lucidum and Z. jujuba improved some antioxidant factors in rats’ adhesion tissues. The result of LC-MS showed that Ganoderma lucidum Karst and Ziziphus jujuba Mill consist of components with antioxidant activity, including ganoderic acid, lucidenic acid, quercetin, linoleic acid, malic acid, and benzoic acid. Conclusion: The results have demonstrated the therapeutic potential of G. lucidum and Z. jujuba in reducing peritoneal adhesion through anti-inflammatory and anti-fibrotic properties, indicating their promising value as a new therapeutic approach in preventing postsurgical adhesion.
{"title":"The Therapeutic Potential of Ganoderma lucidum Karst and Ziziphus jujuba Mill for Postsurgical Adhesion Band Formation","authors":"Ghazaleh Khalili-Tanha, Seyedeh Elnaz Nazari, Fereshteh Asgharzadeh, Leila Mobasheri, Maryam Babaei, Hamideh Naimi, Mina Maftooh, Seyed Mahdi Hassanian, Moein Eskandari, Mohammad-Mostafa Askarnia-Faal, Maryam Alaei, Hamid Reza Ghorbani, Mohsen Aliakbarian, Gordon Ferns, Majid Khazaei, Amir Avan","doi":"10.2174/0115701808298079240818170758","DOIUrl":"https://doi.org/10.2174/0115701808298079240818170758","url":null,"abstract":"Background: Intra-abdominal adhesions are a commonly occurring postoperative complication following abdominopelvic surgery. Peritoneal adhesion formation can lead to infertility, chronic pelvic pain, and intestinal obstruction. The anti-inflammatory and anti-oxidant activities of Ganoderma lucidum Karst (G. lucidum) and Ziziphus jujuba Mill (Z. jujuba) have been reported. Here, we have explored the therapeutic potential of Ganoderma lucidum Karst (G. lucidum) and Z. jujuba against postsurgical adhesion band formation. The NC3Rs ARRIVE guidelines were followed during experimental studies. Methods: G. lucidum powder (800 mg/kg) and Z. jujuba powder (400 mg/kg) were administered using oral gavage to different groups of male albino Wistar rats. After ten days of treatment, macroscopic evidence for peritoneal adhesions and adhesion band score were determined. Furthermore, the anti-inflammatory and antifibrosis effects of G. lucidum and Z. jujuba were assessed using histopathology, ELISA, and real-time polymerase chain reaction methods. Also, alterations in some oxidative stress parameters were evaluated. Results: G. lucidum and Z. jujuba significantly decreased adhesion bands and were associated with a reduction in inflammatory cell infiltration into damaged tissues and the mRNA and protein expression of inflammatory cytokines via modulation of TNF-α, IL-6, IL-1β, and TGF-β. Moreover, both agents inhibited fibrotic adhesion band formation by decreasing collagen deposition and reducing profibrotic marker expression, Col1A1, at the peritoneum adhesion tissues. G. lucidum and Z. jujuba improved some antioxidant factors in rats’ adhesion tissues. The result of LC-MS showed that Ganoderma lucidum Karst and Ziziphus jujuba Mill consist of components with antioxidant activity, including ganoderic acid, lucidenic acid, quercetin, linoleic acid, malic acid, and benzoic acid. Conclusion: The results have demonstrated the therapeutic potential of G. lucidum and Z. jujuba in reducing peritoneal adhesion through anti-inflammatory and anti-fibrotic properties, indicating their promising value as a new therapeutic approach in preventing postsurgical adhesion.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192111","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: AHR and its signaling pathways are promising therapeutic targets for psoriasis. Recent studies in traditional Chinese medicine have confirmed that Indirubin acts as an efficient ligand of AHR, inhibiting the inflammatory response. Clarifying its mechanism of action remains essential. Objective: This study uses bioinformatics to predict Indirubin’s potential molecular mechanism in treating psoriasis and validate the results in animal models. Methods: Indirubin and psoriasis-related targets were screened using the TCMPSP, GeneCards, and OMIM databases. Using the STRING database, a network was constructed and enriched for target protein function. Imiquimod was used to validate the core targets in a psoriasis-like mouse model. Results: Network pharmacology suggested that indirubin targets pathways mainly involved in cancer, inflammation, apoptosis, and other disease mechanisms, including PI3K-Akt, IL-17, and TNF pathways related to psoriasis pathogenesis. Indirubin significantly affected the severity of imiquimod-induced skin lesions in psoriasis-like mice. It also inhibited the expression of IL-6 and il- 1β inflammatory factors and rescued p65 and p-p65 expressions in psoriasis-like mice. Conclusion: Network pharmacology, combined with in vitro cellular experiments, tentatively confirmed that Indirubin reduces the inflammatory response in psoriasis-like mice through the AHR/NF- κB signaling pathway.
{"title":"Indirubin as an AHR Ligand: A Combined Network Pharmacology and Experimental Approach to Psoriasis Therapy","authors":"Lihong Yang, Xueli Cheng, Qian Li, Guandong Liu, Yu Lin, Muchen Xu, Wen Sun, Jing Liu","doi":"10.2174/0115701808316043240718070156","DOIUrl":"https://doi.org/10.2174/0115701808316043240718070156","url":null,"abstract":"Background: AHR and its signaling pathways are promising therapeutic targets for psoriasis. Recent studies in traditional Chinese medicine have confirmed that Indirubin acts as an efficient ligand of AHR, inhibiting the inflammatory response. Clarifying its mechanism of action remains essential. Objective: This study uses bioinformatics to predict Indirubin’s potential molecular mechanism in treating psoriasis and validate the results in animal models. Methods: Indirubin and psoriasis-related targets were screened using the TCMPSP, GeneCards, and OMIM databases. Using the STRING database, a network was constructed and enriched for target protein function. Imiquimod was used to validate the core targets in a psoriasis-like mouse model. Results: Network pharmacology suggested that indirubin targets pathways mainly involved in cancer, inflammation, apoptosis, and other disease mechanisms, including PI3K-Akt, IL-17, and TNF pathways related to psoriasis pathogenesis. Indirubin significantly affected the severity of imiquimod-induced skin lesions in psoriasis-like mice. It also inhibited the expression of IL-6 and il- 1β inflammatory factors and rescued p65 and p-p65 expressions in psoriasis-like mice. Conclusion: Network pharmacology, combined with in vitro cellular experiments, tentatively confirmed that Indirubin reduces the inflammatory response in psoriasis-like mice through the AHR/NF- κB signaling pathway.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192168","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 : 2024-08-13DOI: 10.2174/0115701808306828240808095807
Yao Yao, Wen-Wei Pang, An-Zheng Hu, Hai-Yan Chen, Zhong-Quan Qi
Background: It has been reported that PKCθ plays an important role in the immune response by regulating the cellular activity of T cells and, thus, the production of immune factors such as IL-2.PKCθ protein is mainly expressed in T lymphocytes but not much in other cells and has a very good specificity. Therefore, it is very meaningful to use PKCθ protein as a novel target for immunosuppression. PKCθ is a valuable target that can be used to develop meaningful novel selective immunosuppressive agents. Methods: In this study, we constructed a 3-characteristic pharmacophore（RHA）and used it to perform a virtual screening of the database. Then, we performed a molecular docking analysis of the compounds that scored high. The top five compounds with molecular docking scores were used as lead compounds, and structure-based ligand design via fragment substitution was applied to them, resulting in 20077 new compounds. We performed molecular docking analysis, binding free energy calculations, molecular dynamics simulation, and ADMET prediction on these new compounds and finally identified two compounds as new PKCθ inhibitors. Results and Discussions: Through the screening of pharmacophore, molecular design based on fragment substitution, molecular docking, we finally obtained two small molecules with higher scores than the positive control, in which the molecular docking score of P01 was -53.88 kcal/mol, and the molecular docking score of P02 was -51.20 kcal/mol, and then we performed the molecular dynamics simulation, free energy of binding calculations, and the prediction of ADMET properties for the compounds. The results showed that the ligands could form more stable complexes with the proteins, the binding free energy calculations of the ligand molecules were better than the positive control, all of them had good ADMET properties, and the compounds all had good drug similarity. Conclusion: Our results provided 2 new ligands that could serve as lead compounds for new PKCθ inhibitors in the future.
{"title":"Exploring New Potential Pkcθ Inhibitors Using Pharmacophore Modeling, Molecular Docking Analysis, and Molecular Dynamics Simulations","authors":"Yao Yao, Wen-Wei Pang, An-Zheng Hu, Hai-Yan Chen, Zhong-Quan Qi","doi":"10.2174/0115701808306828240808095807","DOIUrl":"https://doi.org/10.2174/0115701808306828240808095807","url":null,"abstract":"Background: It has been reported that PKCθ plays an important role in the immune response by regulating the cellular activity of T cells and, thus, the production of immune factors such as IL-2.PKCθ protein is mainly expressed in T lymphocytes but not much in other cells and has a very good specificity. Therefore, it is very meaningful to use PKCθ protein as a novel target for immunosuppression. PKCθ is a valuable target that can be used to develop meaningful novel selective immunosuppressive agents. Methods: In this study, we constructed a 3-characteristic pharmacophore（RHA）and used it to perform a virtual screening of the database. Then, we performed a molecular docking analysis of the compounds that scored high. The top five compounds with molecular docking scores were used as lead compounds, and structure-based ligand design via fragment substitution was applied to them, resulting in 20077 new compounds. We performed molecular docking analysis, binding free energy calculations, molecular dynamics simulation, and ADMET prediction on these new compounds and finally identified two compounds as new PKCθ inhibitors. Results and Discussions: Through the screening of pharmacophore, molecular design based on fragment substitution, molecular docking, we finally obtained two small molecules with higher scores than the positive control, in which the molecular docking score of P01 was -53.88 kcal/mol, and the molecular docking score of P02 was -51.20 kcal/mol, and then we performed the molecular dynamics simulation, free energy of binding calculations, and the prediction of ADMET properties for the compounds. The results showed that the ligands could form more stable complexes with the proteins, the binding free energy calculations of the ligand molecules were better than the positive control, all of them had good ADMET properties, and the compounds all had good drug similarity. Conclusion: Our results provided 2 new ligands that could serve as lead compounds for new PKCθ inhibitors in the future.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142192108","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 : 2024-08-02DOI: 10.2174/0115701808299889240722114041
Rafat M. Mohareb, Maken Mohamed Ahmed
Background: In the field of pharmaceutical chemistry, the anti-cancer activity of such compounds received great attention. For both medicinal and industrial studies,, xanthene derivatives are important compounds that have had many applications that have enhanced their use in recent years. Xanthene and its derivatives are extensively used scaffolds in drug designing and the development of novel anti-cancer agents due to their large pharmaceutical applications. Objective: The 3,3-dimethyl-2,3-dihydro-1H-xanthen-1-one was used to synthesise anti-cancer agents of fused pyran, pyridine, pyridazine, and thiophene derivatives. As the potentially privileged scaffolds, xanthene-fused bicyclic heterocycles may be used to discover new drugs with similar biological targets and improved therapeutic efficacy. Method: The key starting compound 3,3-dimethyl-2,3-dihydro-1H-xanthen-1-one was used in many heterocyclization reactions through its reactions with different reagents like aryldiazonium salts, reaction with S8 and producing fused tetracyclic compounds. Results: Through this work, new compounds were synthesized and, characterized, and evaluated toward the six cancer cell lines, namely A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460. The inhibitions on tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR for selected compounds were studied and the results were supplied by studying the mechanism of action toward EGFR. Furthermore, the morphological changes of selected cell lines by the effect of compounds 6b and 13c were studied. Conclusion: We focused our attention on the synthesis of heterocyclic compounds based on xanthene moiety. After a detailed optimization study, many of the synthesized compounds can be considered anticancer agents, enhancing further studies.
{"title":"Synthesis and Anti-proliferative, Tyrosine Kinases Inhibitions of New Xanthene Derivatives and their Morphological Studies","authors":"Rafat M. Mohareb, Maken Mohamed Ahmed","doi":"10.2174/0115701808299889240722114041","DOIUrl":"https://doi.org/10.2174/0115701808299889240722114041","url":null,"abstract":"Background: In the field of pharmaceutical chemistry, the anti-cancer activity of such compounds received great attention. For both medicinal and industrial studies,, xanthene derivatives are important compounds that have had many applications that have enhanced their use in recent years. Xanthene and its derivatives are extensively used scaffolds in drug designing and the development of novel anti-cancer agents due to their large pharmaceutical applications. Objective: The 3,3-dimethyl-2,3-dihydro-1H-xanthen-1-one was used to synthesise anti-cancer agents of fused pyran, pyridine, pyridazine, and thiophene derivatives. As the potentially privileged scaffolds, xanthene-fused bicyclic heterocycles may be used to discover new drugs with similar biological targets and improved therapeutic efficacy. Method: The key starting compound 3,3-dimethyl-2,3-dihydro-1H-xanthen-1-one was used in many heterocyclization reactions through its reactions with different reagents like aryldiazonium salts, reaction with S8 and producing fused tetracyclic compounds. Results: Through this work, new compounds were synthesized and, characterized, and evaluated toward the six cancer cell lines, namely A549, HT-29, MKN-45, U87MG, and SMMC-7721 and H460. The inhibitions on tyrosine kinases c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR for selected compounds were studied and the results were supplied by studying the mechanism of action toward EGFR. Furthermore, the morphological changes of selected cell lines by the effect of compounds 6b and 13c were studied. Conclusion: We focused our attention on the synthesis of heterocyclic compounds based on xanthene moiety. After a detailed optimization study, many of the synthesized compounds can be considered anticancer agents, enhancing further studies.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-08-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141883142","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 : 2024-07-30DOI: 10.2174/0115701808291656240722095841
Jin-Rong Ma, Qiu-Rong Huang, Ruo-Jun Man, Lin-Guo Zhao, Dong-Dong Li
Introduction: Berberine is an important isoquinoline alkaloid that has various pharmacological properties. The comparison of the binding pocket similarity of berberine is regarded as the starting point for deciphering various activities. Eight berberine protein crystals were clustered and studied by molecular dynamics (MD) simulations to investigate common features of berberine binding pockets. Method: Root Mean Square Deviation (RMSD) results showed that berberine was able to bind to each protein in a stable manner. Residue analysis showed that the stability of residue composition of different protein pockets varied. This is also consistent with the results of the pocket similarity analysis: PS-score curves of most proteins fluctuated to varying degrees. The binding pocket of 3BTI in homogeneous protein analysis exhibited high stability (PS-scoremean = 0.703 and PS-scoremin = 0.5664). Pocket similarity analysis between two heterologous proteins showed that most of PS-score values were in the interval of 0.3-0.35, and PS-score values of 3D6Y were relatively high when compared with the other three proteins. Results: Pocket residue matching analysis showed that GLU145/VAL147/ILE182/TYR229/GLU253 in 3D6Y can be matched structurally to the corresponding residues in 1JUM, 2QVD, and 5Y0V, respectively, which can be considered as an important pocket feature for the berberine binding. Nevertheless, the obtained matched residues are limited to the category of pocket structural similarity. Conclusion: This was the first study in which dynamic comparison of berberine binding pockets were used to discover pocket patterns. These results were of great significance for the polypharmacological study, the identification of potential off-targets, and the repurposing of berberine. conclusion: This was the first study in which dynamic comparisons of berberine binding pockets were used to discover interaction patterns. These results were of great significance for the polypharmacological study, the identification of potential off-targets, and the repurposing of berberine.
{"title":"Dynamic Comparison of Binding Pocket of Berberine Protein Crystals","authors":"Jin-Rong Ma, Qiu-Rong Huang, Ruo-Jun Man, Lin-Guo Zhao, Dong-Dong Li","doi":"10.2174/0115701808291656240722095841","DOIUrl":"https://doi.org/10.2174/0115701808291656240722095841","url":null,"abstract":"Introduction: Berberine is an important isoquinoline alkaloid that has various pharmacological properties. The comparison of the binding pocket similarity of berberine is regarded as the starting point for deciphering various activities. Eight berberine protein crystals were clustered and studied by molecular dynamics (MD) simulations to investigate common features of berberine binding pockets. Method: Root Mean Square Deviation (RMSD) results showed that berberine was able to bind to each protein in a stable manner. Residue analysis showed that the stability of residue composition of different protein pockets varied. This is also consistent with the results of the pocket similarity analysis: PS-score curves of most proteins fluctuated to varying degrees. The binding pocket of 3BTI in homogeneous protein analysis exhibited high stability (PS-scoremean = 0.703 and PS-scoremin = 0.5664). Pocket similarity analysis between two heterologous proteins showed that most of PS-score values were in the interval of 0.3-0.35, and PS-score values of 3D6Y were relatively high when compared with the other three proteins. Results: Pocket residue matching analysis showed that GLU145/VAL147/ILE182/TYR229/GLU253 in 3D6Y can be matched structurally to the corresponding residues in 1JUM, 2QVD, and 5Y0V, respectively, which can be considered as an important pocket feature for the berberine binding. Nevertheless, the obtained matched residues are limited to the category of pocket structural similarity. Conclusion: This was the first study in which dynamic comparison of berberine binding pockets were used to discover pocket patterns. These results were of great significance for the polypharmacological study, the identification of potential off-targets, and the repurposing of berberine. conclusion: This was the first study in which dynamic comparisons of berberine binding pockets were used to discover interaction patterns. These results were of great significance for the polypharmacological study, the identification of potential off-targets, and the repurposing of berberine.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141866826","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: Postoperative adhesions commonly occur after abdominal surgery and can lead to significant complications. There is increasing evidence that targeting the renin-angiotensin system (RAS) can reduce inflammation and fibrosis. This study investigates the therapeutic potential of enalapril, an RAS inhibitor, in a rat model of postsurgical adhesion band formation. Methods: A total of 12 male albino Wistar rats received intraperitoneal administration of enalapril (10 mg/kg). After 9 days, the anti-inflammatory and antifibrotic effects were evaluated using RTPCR and ELISA, alongside hematoxylin and eosin and Masson's trichrome staining. Result: The statistical analysis of findings showed that enalapril significantly reduced the frequency and stability of adhesion bands. It attenuated submucosal edema by suppressing pro-inflammatory cytokines, decreasing pro-inflammatory cell infiltration, and inhibiting oxidative stress at the peritoneal surgery site. Additionally, enalapril inhibited fibrotic adhesion band formation by reducing collagen deposition and suppressing the expression of profibrotic genes in peritoneal adhesion tissues. Conclusion: These findings demonstrate the therapeutic potential of enalapril in preventing postsurgical adhesion band formation by inhibiting key pathological responses of inflammation and fibrosis, supporting its use as a preventive treatment in postoperative adhesion management.
{"title":"Targeting Angiotensin-converting Enzyme Inhibitor via Enalapril Reduces Postsurgical Adhesion Band Formation","authors":"Sanaz Majnoon, Fereshteh Asgharzadeh, Reihaneh Sabbaghzadeh, Seyede Elnaz Nazari, Zahra Yarmohammadi, Nikoo Saeedi, Seyed Mahdi Hassanian, Gordon Ferns, Majid Khazaei, Amir Avan","doi":"10.2174/0115701808293346240726110944","DOIUrl":"https://doi.org/10.2174/0115701808293346240726110944","url":null,"abstract":"Background: Postoperative adhesions commonly occur after abdominal surgery and can lead to significant complications. There is increasing evidence that targeting the renin-angiotensin system (RAS) can reduce inflammation and fibrosis. This study investigates the therapeutic potential of enalapril, an RAS inhibitor, in a rat model of postsurgical adhesion band formation. Methods: A total of 12 male albino Wistar rats received intraperitoneal administration of enalapril (10 mg/kg). After 9 days, the anti-inflammatory and antifibrotic effects were evaluated using RTPCR and ELISA, alongside hematoxylin and eosin and Masson's trichrome staining. Result: The statistical analysis of findings showed that enalapril significantly reduced the frequency and stability of adhesion bands. It attenuated submucosal edema by suppressing pro-inflammatory cytokines, decreasing pro-inflammatory cell infiltration, and inhibiting oxidative stress at the peritoneal surgery site. Additionally, enalapril inhibited fibrotic adhesion band formation by reducing collagen deposition and suppressing the expression of profibrotic genes in peritoneal adhesion tissues. Conclusion: These findings demonstrate the therapeutic potential of enalapril in preventing postsurgical adhesion band formation by inhibiting key pathological responses of inflammation and fibrosis, supporting its use as a preventive treatment in postoperative adhesion management.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-07-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141866827","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 : 2024-07-18DOI: 10.2174/0115701808306787240709073814
Assia Guendouze, El Hassen Mokrani, Ouided Benslama, Sabrina Lekmine
Background: Optimal glycemic control is crucial in type 2 diabetes treatment, with αglucosidase inhibitors emerging as promising candidates. Avenanthramides, compounds found in oats, exhibit therapeutic potential, but their efficacy as α-glucosidase inhibitors requires thorough evaluation. Objective: This study investigates the potential of avenanthramides and their derivatives as inhibitors of α-glucosidase for the treatment of type 2 diabetes through comprehensive computational analysis. Methods: Structure-Based Virtual Screening of 3543 avenanthramides and their analog compounds was conducted using FlexX. The top 30 ranked compounds were subjected to visual inspection of their binding mode within the α-glucosidase binding site to eliminate false positives. The top-ranked molecule was subjected to dynamic simulation and ADMET prediction. Results: The results revealed that 1634 compounds were found to exhibit a greater α-glucosidase inhibitory potency than miglitol, the reference molecule. Compound S1 exhibited superior αglucosidase inhibitory potency with a binding energy of -45.7786 kJ/mol compared to miglitol, which had a binding energy of -26.5186 kJ/mol. S1 was predicted to occupy the entire binding site with an optimized number of hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations demonstrated that S1 had a lower average RMSD (0.15 ± 0.01 nm) compared to miglitol (0.16 ± 0.01 nm), indicating superior stability within the α-glucosidase binding site. S1 exhibited favorable drug-like properties, suggesting its potential as a lead compound for further development in type 2 diabetes treatment. Conclusion: These findings highlight S1's potential for diabetes treatment and pave the way for future experimental investigations. The computational approach utilized offers valuable insights into the inhibitory potential of avenanthramides, providing a foundation for further drug development for type 2 diabetes.
{"title":"Exploring the Potential of Avenanthramides and their Analogues as α-Glucosidase Inhibitors for Type 2 Diabetes Treatment Utilizing Virtual Screening, Molecular Dynamics, and Drug-likeness Predictions","authors":"Assia Guendouze, El Hassen Mokrani, Ouided Benslama, Sabrina Lekmine","doi":"10.2174/0115701808306787240709073814","DOIUrl":"https://doi.org/10.2174/0115701808306787240709073814","url":null,"abstract":"Background: Optimal glycemic control is crucial in type 2 diabetes treatment, with αglucosidase inhibitors emerging as promising candidates. Avenanthramides, compounds found in oats, exhibit therapeutic potential, but their efficacy as α-glucosidase inhibitors requires thorough evaluation. Objective: This study investigates the potential of avenanthramides and their derivatives as inhibitors of α-glucosidase for the treatment of type 2 diabetes through comprehensive computational analysis. Methods: Structure-Based Virtual Screening of 3543 avenanthramides and their analog compounds was conducted using FlexX. The top 30 ranked compounds were subjected to visual inspection of their binding mode within the α-glucosidase binding site to eliminate false positives. The top-ranked molecule was subjected to dynamic simulation and ADMET prediction. Results: The results revealed that 1634 compounds were found to exhibit a greater α-glucosidase inhibitory potency than miglitol, the reference molecule. Compound S1 exhibited superior αglucosidase inhibitory potency with a binding energy of -45.7786 kJ/mol compared to miglitol, which had a binding energy of -26.5186 kJ/mol. S1 was predicted to occupy the entire binding site with an optimized number of hydrogen bonds and hydrophobic interactions. Molecular dynamics simulations demonstrated that S1 had a lower average RMSD (0.15 ± 0.01 nm) compared to miglitol (0.16 ± 0.01 nm), indicating superior stability within the α-glucosidase binding site. S1 exhibited favorable drug-like properties, suggesting its potential as a lead compound for further development in type 2 diabetes treatment. Conclusion: These findings highlight S1's potential for diabetes treatment and pave the way for future experimental investigations. The computational approach utilized offers valuable insights into the inhibitory potential of avenanthramides, providing a foundation for further drug development for type 2 diabetes.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141739133","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}
Objective: This study aimed to assess the combinational antidiabetic effect of catechin and metformin in streptozotocin (STZ)-induced diabetic rats. Methods: Wistar rats were chosen and divided into five groups (n=6). STZ at the dose of 55 mg/kg was used intraperitoneally for the induction of diabetes. The combination of catechin (CTN) and metformin (MET) was administered to diabetic rats. The changes in fasting blood sugar, body weight, Hb, HbA1c, creatinine, lipid profiles (TC, HDL, LDL, and TG), biochemical parameters (SGOT, SGPT, and ALP), and endogenous antioxidant parameters (SOD, GSH, and catalase) were assessed. Histopathological study of the β-cells in islets of the pancreas, kidney tubules, and liver cells was conducted in all groups. Results: The result showed a significant reduction (p < 0.001) in blood sugar in the CTN and METtreated group compared to the control group. The combination of CTN (50 mg/kg) and MET (22.5 mg/kg) significantly restored the creatinine levels and urine volumes, SGOT, SGPT, and ALP, compared to a single administration dose. The abnormal lipid profile levels (TC, LDL, TG, and HDL) and antioxidant enzymes (SOD, GSH, catalase) in diabetic control rats were restored to average levels in a significant manner. Histopathological results revealed significant alterations, including hypertrophy of islets and mild degeneration, renal necrosis, and inflammation of hepatocytes. Conclusion: The findings indicate that a combination of therapy (CTN+MET) improved the protective effect of the pancreas, kidney, and liver, suggesting that the combination shows a potential antidiabetic effect.
{"title":"A Combination of Catechin and Metformin: Its Preclinical Efficacy and Safety in STZ-Induced Diabetic Rats","authors":"Jyoshna Rani Dash, Gurudutta Pattnaik, Ashirbad Nanda, Goutam Ghosh, Goutam Rath, Biswakanth Kar","doi":"10.2174/0115701808304505240628103332","DOIUrl":"https://doi.org/10.2174/0115701808304505240628103332","url":null,"abstract":"Objective: This study aimed to assess the combinational antidiabetic effect of catechin and metformin in streptozotocin (STZ)-induced diabetic rats. Methods: Wistar rats were chosen and divided into five groups (n=6). STZ at the dose of 55 mg/kg was used intraperitoneally for the induction of diabetes. The combination of catechin (CTN) and metformin (MET) was administered to diabetic rats. The changes in fasting blood sugar, body weight, Hb, HbA1c, creatinine, lipid profiles (TC, HDL, LDL, and TG), biochemical parameters (SGOT, SGPT, and ALP), and endogenous antioxidant parameters (SOD, GSH, and catalase) were assessed. Histopathological study of the β-cells in islets of the pancreas, kidney tubules, and liver cells was conducted in all groups. Results: The result showed a significant reduction (p < 0.001) in blood sugar in the CTN and METtreated group compared to the control group. The combination of CTN (50 mg/kg) and MET (22.5 mg/kg) significantly restored the creatinine levels and urine volumes, SGOT, SGPT, and ALP, compared to a single administration dose. The abnormal lipid profile levels (TC, LDL, TG, and HDL) and antioxidant enzymes (SOD, GSH, catalase) in diabetic control rats were restored to average levels in a significant manner. Histopathological results revealed significant alterations, including hypertrophy of islets and mild degeneration, renal necrosis, and inflammation of hepatocytes. Conclusion: The findings indicate that a combination of therapy (CTN+MET) improved the protective effect of the pancreas, kidney, and liver, suggesting that the combination shows a potential antidiabetic effect.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141609638","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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