Pub Date : 2020-07-28DOI: 10.2174/2212796814999200728185759
Abhishek Kumar, N. Masand, V. Patil
Breast cancer is the most common and highly heterogeneous neoplastic disease comprised of several subtypes with distinct molecular etiology and clinical behaviours. The mortality observed over the past few decades and the failure in eradicating the disease is due to the lack of specific etiology, molecular mechanisms involved in the initiation and progression of breast cancer. Understanding of the molecular classes of breast cancer may also lead to new biological insights and eventually to better therapies. The promising therapeutic targets and novel anti-cancer approaches emerging from these molecular targets that could be applied clinically in the near future are being highlighted. In addition, this review discusses some of the details of current molecular classification and available chemotherapeutics.
{"title":"Understanding Molecular Process and Chemotherapeutics for the Management of Breast Cancer","authors":"Abhishek Kumar, N. Masand, V. Patil","doi":"10.2174/2212796814999200728185759","DOIUrl":"https://doi.org/10.2174/2212796814999200728185759","url":null,"abstract":"\u0000\u0000Breast cancer is the most common and highly heterogeneous neoplastic disease\u0000comprised of several subtypes with distinct molecular etiology and clinical behaviours. The\u0000mortality observed over the past few decades and the failure in eradicating the disease is due\u0000to the lack of specific etiology, molecular mechanisms involved in the initiation and progression\u0000of breast cancer. Understanding of the molecular classes of breast cancer may also lead\u0000to new biological insights and eventually to better therapies. The promising therapeutic targets\u0000and novel anti-cancer approaches emerging from these molecular targets that could be\u0000applied clinically in the near future are being highlighted. In addition, this review discusses\u0000some of the details of current molecular classification and available chemotherapeutics.\u0000","PeriodicalId":10784,"journal":{"name":"Current Chemical Biology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90314048","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 : 2020-06-09DOI: 10.2174/2212796814999200609131623
Imane Bjij, Ismail Hdoufane, M. Soliman, Menče Najdoska-Bogdanov, D. Cherqaoui
The ubiquitin proteasome system (UPS) is a crucial protein degradation pathway that involves several enzymes to maintain cellular protein homeostasis. This system has emerged as a major drug target against certain types of cancer as a disruption at the cellular level of UPS enzyme components forces the transformation of normal cell into cancerous cell. Although enormous advancements have been achieved in the understanding of tumorigenesis, efficient cancer therapy remains a goal towards alleviating this serious health issue. Since UPS has become a promising target for anticancer therapies, herein, we provide comprehensive review of the ubiquitin proteasome system as a significant process for protein degradation. Herein, the anti-cancer therapeutic potential of this pathway is also discussed.
{"title":"Targeting Protein Degradation in Cancer Treatment","authors":"Imane Bjij, Ismail Hdoufane, M. Soliman, Menče Najdoska-Bogdanov, D. Cherqaoui","doi":"10.2174/2212796814999200609131623","DOIUrl":"https://doi.org/10.2174/2212796814999200609131623","url":null,"abstract":"\u0000\u0000The ubiquitin proteasome system (UPS) is a crucial protein degradation pathway\u0000that involves several enzymes to maintain cellular protein homeostasis. This system has\u0000emerged as a major drug target against certain types of cancer as a disruption at the cellular\u0000level of UPS enzyme components forces the transformation of normal cell into cancerous\u0000cell. Although enormous advancements have been achieved in the understanding of tumorigenesis,\u0000efficient cancer therapy remains a goal towards alleviating this serious health issue.\u0000Since UPS has become a promising target for anticancer therapies, herein, we provide comprehensive\u0000review of the ubiquitin proteasome system as a significant process for protein\u0000degradation. Herein, the anti-cancer therapeutic potential of this pathway is also discussed.\u0000","PeriodicalId":10784,"journal":{"name":"Current Chemical Biology","volume":"9 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78352243","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 : 2020-02-29DOI: 10.2174/2212796814666200310100746
M. Dwivedi
Scientific interest in mycobacteria has been sparked by the medical importance of Mycobacterium tuberculosis (Mtb) that is known to cause severe diseases in mammals, i.e. tuberculosis and by properties that distinguish them from other microorganisms which are notoriously difficult to treat. The treatment of their infections is difficult because mycobacteria fortify themselves with a thick impermeable cell envelope. Channel and transporter proteins are among the crucial adaptations of Mycobacterium that facilitate their strength to combat against host immune system and anti-tuberculosis drugs. In previous studies, it was investigated that some of the channel proteins contribute to the overall antibiotic resistance in Mtb. Moreover, in some of the cases, membrane proteins were found responsible for virulence of these pathogens. Given the ability of M. tuberculosis to survive as an intracellular pathogen and its inclination to develop resistance to the prevailing anti-tuberculosis drugs, its treatment requires new approaches and optimization of anti-TB drugs and investigation of new targets are needed for their potential in clinical usage. Therefore, it is imperative to investigate the survival of Mtb. in stressed conditions with different behavior of particular channel/ transporter proteins. Comprehensive understanding of channel proteins and their mechanism will provide us direction to find out preventive measures against the emergence of resistance and reduce the duration of the treatment, eventually leading to plausible eradication of tuberculosis.
{"title":"Exploration of Ion Channels in Mycobacterium tuberculosis: Implication on Drug Discovery and Potent Drug Targets Against Tuberculosis","authors":"M. Dwivedi","doi":"10.2174/2212796814666200310100746","DOIUrl":"https://doi.org/10.2174/2212796814666200310100746","url":null,"abstract":"Scientific interest in mycobacteria has been sparked by the medical importance of Mycobacterium tuberculosis (Mtb) that is known to cause severe diseases in mammals, i.e. tuberculosis and by properties that distinguish them from other microorganisms which are notoriously difficult to treat. The treatment of their infections is difficult because mycobacteria fortify themselves with a thick impermeable cell envelope. Channel and transporter proteins are among the crucial adaptations of Mycobacterium that facilitate their strength to combat against host immune system and anti-tuberculosis drugs. In previous studies, it was investigated that some of the channel proteins contribute to the overall antibiotic resistance in Mtb. Moreover, in some of the cases, membrane proteins were found responsible for virulence of these pathogens. Given the ability of M. tuberculosis to survive as an intracellular pathogen and its inclination to develop resistance to the prevailing anti-tuberculosis drugs, its treatment requires new approaches and optimization of anti-TB drugs and investigation of new targets are needed for their potential in clinical usage. Therefore, it is imperative to investigate the survival of Mtb. in stressed conditions with different behavior of particular channel/ transporter proteins. Comprehensive understanding of channel proteins and their mechanism will provide us direction to find out preventive measures against the emergence of resistance and reduce the duration of the treatment, eventually leading to plausible eradication of tuberculosis.","PeriodicalId":10784,"journal":{"name":"Current Chemical Biology","volume":"31 1","pages":"14-29"},"PeriodicalIF":0.0,"publicationDate":"2020-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80159513","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 : 2020-02-29DOI: 10.2174/2212796813666191111142824
E. El-Shafey, E. Elsherbiny
Autophagy is a well-maintained process by which the cells recycle intracellular materials to maintain homeostasis in various cellular functions. However, autophagy is a defensive mechanism that maintains cell survival under antagonistic conditions, the induction of the autophagic process may substantially lead to cell death. The conflicting roles of autophagy including allowing cell survival or promoting cell death could have a troublesome impact on the efficiency of chemotherapeutic agents. Accordingly, understanding the role of autophagy in cancer is a vital need for its optimal manipulation in therapy.
{"title":"Dual Opposed Survival-supporting and Death-promoting Roles of Autophagy in Cancer Cells: A Concise Review","authors":"E. El-Shafey, E. Elsherbiny","doi":"10.2174/2212796813666191111142824","DOIUrl":"https://doi.org/10.2174/2212796813666191111142824","url":null,"abstract":"\u0000\u0000Autophagy is a well-maintained process by which the cells recycle intracellular\u0000materials to maintain homeostasis in various cellular functions. However, autophagy is a defensive\u0000mechanism that maintains cell survival under antagonistic conditions, the induction\u0000of the autophagic process may substantially lead to cell death. The conflicting roles of autophagy\u0000including allowing cell survival or promoting cell death could have a troublesome impact\u0000on the efficiency of chemotherapeutic agents. Accordingly, understanding the role of\u0000autophagy in cancer is a vital need for its optimal manipulation in therapy.\u0000","PeriodicalId":10784,"journal":{"name":"Current Chemical Biology","volume":"85 1","pages":"4-13"},"PeriodicalIF":0.0,"publicationDate":"2020-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83906422","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 : 2020-02-29DOI: 10.2174/2212796813666191118100520
Dattatraya G. Raut, S. Patil, P. Choudhari, Vikas D. Kadu, A. Lawand, M. Hublikar, R. Bhosale
The present research work is focused on the development of alternative antioxidant and anti-inflammatory agents. The review of the literature reveals that many benzofused thiazole analogues have been used as lead molecules for the design and development of therapeutic agent, including anticancer, anti-inflammatory, antioxidant and antiviral. The synthesized benzofused thiazole derivatives are evaluated for in vitro antioxidant, anti-inflammatory activities and molecular docking study. Thus, the present research work aims to synthesize benzofused thiazole derivatives and to test their antioxidant and antiinflammatory activities. To design and synthesize an alternative antioxidant and anti-inflammatory agents. The substituted benzofused thiazoles 3a-g were prepared by cyclocondensation reaction of appropriate carboxylic acid with 2-aminothiophenol in POCl3 and heated for about 2-3 h to offer benzofused thiazole derivatives 3a-g. All the newly synthesized compounds were in vitro screened for their anti-inflammatory and antioxidant activities by using a known literature method. At the outset, the study of in vitro indicated that the compounds code 3c, 3d and 3e possessed distinct anti-inflammatory activity as compared to a standard reference. All the tested compounds show potential antioxidant activity against one or more reactive (H2O2, DPPH, SO and NO) radical scavenging species. Additionally, docking simulation is further performed to the position of compounds 3d & 3e into the anti-inflammatory active site to determine the probable binding model. New anti-inflammatory and antioxidant agents were needed; it has been proved that benzofused thiazole derivatives were 3c, 3d and 3e constituted as an interesting template for the evaluation of new anti-inflammatory agents and an antioxidant’s work also may provide an interesting template for further development.
{"title":"POCl3 Mediated Syntheses, Pharmacological Evaluation and Molecular Docking Studies of Some Novel Benzofused Thiazole Derivatives as a Potential Antioxidant and Anti-inflammatory Agents","authors":"Dattatraya G. Raut, S. Patil, P. Choudhari, Vikas D. Kadu, A. Lawand, M. Hublikar, R. Bhosale","doi":"10.2174/2212796813666191118100520","DOIUrl":"https://doi.org/10.2174/2212796813666191118100520","url":null,"abstract":"\u0000\u0000The present research work is focused on the development of alternative\u0000antioxidant and anti-inflammatory agents. The review of the literature reveals that many\u0000benzofused thiazole analogues have been used as lead molecules for the design and development\u0000of therapeutic agent, including anticancer, anti-inflammatory, antioxidant and antiviral.\u0000The synthesized benzofused thiazole derivatives are evaluated for in vitro antioxidant,\u0000anti-inflammatory activities and molecular docking study. Thus, the present research work\u0000aims to synthesize benzofused thiazole derivatives and to test their antioxidant and antiinflammatory\u0000activities.\u0000\u0000\u0000\u0000To design and synthesize an alternative antioxidant and anti-inflammatory agents.\u0000\u0000\u0000\u0000The substituted benzofused thiazoles 3a-g were prepared by cyclocondensation reaction\u0000of appropriate carboxylic acid with 2-aminothiophenol in POCl3 and heated for about\u00002-3 h to offer benzofused thiazole derivatives 3a-g. All the newly synthesized compounds\u0000were in vitro screened for their anti-inflammatory and antioxidant activities by using a\u0000known literature method.\u0000\u0000\u0000\u0000At the outset, the study of in vitro indicated that the compounds code 3c, 3d and 3e\u0000possessed distinct anti-inflammatory activity as compared to a standard reference. All the\u0000tested compounds show potential antioxidant activity against one or more reactive (H2O2,\u0000DPPH, SO and NO) radical scavenging species. Additionally, docking simulation is further\u0000performed to the position of compounds 3d & 3e into the anti-inflammatory active site to determine\u0000the probable binding model.\u0000\u0000\u0000\u0000New anti-inflammatory and antioxidant agents were needed; it has been proved\u0000that benzofused thiazole derivatives were 3c, 3d and 3e constituted as an interesting template\u0000for the evaluation of new anti-inflammatory agents and an antioxidant’s work also may provide\u0000an interesting template for further development.\u0000","PeriodicalId":10784,"journal":{"name":"Current Chemical Biology","volume":"50 1","pages":"58-68"},"PeriodicalIF":0.0,"publicationDate":"2020-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85127160","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 : 2020-02-29DOI: 10.2174/2212796813666190926112807
A. Abolhasani, F. Heidari, S. Noori, S. Mousavi, H. Abolhasani
3'-(3,4-dimethoxyphenyl)-4'-(4-(methylsulfonyl)phenyl)-4'H-spiro [indene-2,5'-isoxazol]-1(3H)-one and 4'-(4-(methylsulfonyl)phenyl)-3'-(3,4,5-trimethoxyphenyl)- 4'H-spiro[indene-2,5'-isoxazol]-1(3H)-one compounds containing indanonic spiroisoxazoline core are widely known for their antiproliferative activities and investigation of tubulin binding modes. To evaluate the cytotoxicity effect of Dimethoxy and Trimethoxy Indanonic Spiroisoxazolines against HepG2 cancerous liver cell line and to perform a comparison with other known anti-liver cancer drugs. The evaluation of cytotoxicity of dimethoxy and trimethoxy indanonic spiroisoxazoline compounds, Oxaliplatin, Doxorubicin, 5-fluorouracil and Cisplatin against HepG2 (hepatocellular liver carcinoma) cell line has been performed using MTT assay and analyzed by GraphPad PRISM software (version 8.0.2). Potent cytotoxicity effects against HepG2 cell line, comparable to Cisplatin (IC50= 0.047±0.0045 µM), Oxaliplatin (IC50= 0.0051µM), Doxorubicin (IC50= 0.0014µM) and 5- fluorouracil (IC50= 0.0089 µM), were shown by both dimethoxy (IC50= 0.059±0.012 µM) and trimethoxy (IC50= 0.086±0.019 µM) indanonic spiroisoxazoline compounds. In vitro biological evaluations revealed that dimethoxy and trimethoxy indanonic spiroisoxazoline compounds are good candidates for the development of new anti-liver cancer agents.
3'-(3,4-二甲氧基苯基)-4'-(4-(甲基磺酰基)苯基)-4'- h -spiro[茚-2,5'-异恶唑]-1(3H)- 1和4'-(4-(甲基磺酰基)苯基)-3'-(3,4,5-三甲氧基苯基)-4'- h -spiro[茚-2,5'-异恶唑]-1(3H)- 1含有吲哚酮螺的化合物因其抗增殖活性和对微管蛋白结合模式的研究而广为人知。目的评价二甲氧基和三甲氧基吲哚酮螺异恶唑啉对HepG2肝癌细胞株的细胞毒性作用，并与其他已知抗肝癌药物进行比较。采用MTT法评价二甲氧基和三甲氧基茚二酮螺异恶唑啉化合物、奥沙利铂、阿霉素、5-氟尿嘧啶和顺铂对HepG2(肝细胞肝癌)细胞株的细胞毒性，并采用GraphPad PRISM软件(8.0.2版)进行分析。二甲氧基(IC50= 0.059±0.012µM)和三甲氧基(IC50= 0.086±0.019µM)茚二酮螺异恶唑啉化合物对HepG2细胞株的细胞毒作用与顺铂(IC50=0.047±0.0045µM)、奥沙利铂(IC50= 0.0051µM)、阿霉素(IC50= 0.0014µM)和5-氟尿嘧啶(IC50= 0.0089µM)相当。体外生物学评价表明，二甲氧基和三甲氧基吲哚醌螺异恶唑啉类化合物是开发新型抗肝癌药物的良好候选者。
{"title":"Cytotoxicity Evaluation of Dimethoxy and Trimethoxy Indanonic Spiroisoxazolines Against Cancerous Liver Cells","authors":"A. Abolhasani, F. Heidari, S. Noori, S. Mousavi, H. Abolhasani","doi":"10.2174/2212796813666190926112807","DOIUrl":"https://doi.org/10.2174/2212796813666190926112807","url":null,"abstract":"\u0000\u00003'-(3,4-dimethoxyphenyl)-4'-(4-(methylsulfonyl)phenyl)-4'H-spiro\u0000[indene-2,5'-isoxazol]-1(3H)-one and 4'-(4-(methylsulfonyl)phenyl)-3'-(3,4,5-trimethoxyphenyl)-\u00004'H-spiro[indene-2,5'-isoxazol]-1(3H)-one compounds containing indanonic spiroisoxazoline\u0000core are widely known for their antiproliferative activities and investigation of\u0000tubulin binding modes.\u0000\u0000\u0000\u0000To evaluate the cytotoxicity effect of Dimethoxy and Trimethoxy Indanonic Spiroisoxazolines\u0000against HepG2 cancerous liver cell line and to perform a comparison with\u0000other known anti-liver cancer drugs.\u0000\u0000\u0000\u0000 The evaluation of cytotoxicity of dimethoxy and trimethoxy indanonic spiroisoxazoline\u0000compounds, Oxaliplatin, Doxorubicin, 5-fluorouracil and Cisplatin against HepG2\u0000(hepatocellular liver carcinoma) cell line has been performed using MTT assay and analyzed\u0000by GraphPad PRISM software (version 8.0.2).\u0000\u0000\u0000\u0000Potent cytotoxicity effects against HepG2 cell line, comparable to Cisplatin (IC50=\u00000.047±0.0045 µM), Oxaliplatin (IC50= 0.0051µM), Doxorubicin (IC50= 0.0014µM) and 5-\u0000fluorouracil (IC50= 0.0089 µM), were shown by both dimethoxy (IC50= 0.059±0.012 µM)\u0000and trimethoxy (IC50= 0.086±0.019 µM) indanonic spiroisoxazoline compounds.\u0000\u0000\u0000\u0000 In vitro biological evaluations revealed that dimethoxy and trimethoxy indanonic\u0000spiroisoxazoline compounds are good candidates for the development of new anti-liver\u0000cancer agents.\u0000","PeriodicalId":10784,"journal":{"name":"Current Chemical Biology","volume":"34 1","pages":"38-47"},"PeriodicalIF":0.0,"publicationDate":"2020-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87207062","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 : 2020-02-29DOI: 10.2174/2212796814666200122114833
Chiranjib Deb
In human cells, Heat Shock Protein-90 (HSP-90) is present in the cytosol, nucleoplasm, endoplasmic reticulum, and mitochondria. The eukaryotic HSP-90 is multifunctionary and essential for cell viability, signal transduction, cell-cycle control as well as transcriptional regulation. The intracellular environment does not restrict HSP-90. It has a vital role in all types of inflammatory disorders, including cancer, autoimmune diseases, infectious inflammatory conditions. Hence, pharmacological inhibition of HSP-90 is currently a choice of therapeutic target for the treatment of autoimmune diseases, cancer, and infectious diseases. Based on the biology of HSP-90, several COOH-terminal ATPase sites of HSP-90, NH2-terminal ATPase sites of HSP-90, and Histone deacetylase inhibitors are evaluated and classified under various groups. For the treatment of different inflammatory disorders, HSP-90 identified as a promising therapeutic target. The present review may guide researchers for evaluating the HSP-90 targeted pathway as a useful therapeutic target for inflammatory diseases, including cancers.
{"title":"The Role of Heat Shock Protein -90 (HSP-90) in Inflammatory Disorders","authors":"Chiranjib Deb","doi":"10.2174/2212796814666200122114833","DOIUrl":"https://doi.org/10.2174/2212796814666200122114833","url":null,"abstract":"\u0000\u0000In human cells, Heat Shock Protein-90 (HSP-90) is present in the cytosol, nucleoplasm,\u0000endoplasmic reticulum, and mitochondria. The eukaryotic HSP-90 is multifunctionary\u0000and essential for cell viability, signal transduction, cell-cycle control as well as\u0000transcriptional regulation. The intracellular environment does not restrict HSP-90. It has a\u0000vital role in all types of inflammatory disorders, including cancer, autoimmune diseases, infectious\u0000inflammatory conditions. Hence, pharmacological inhibition of HSP-90 is currently\u0000a choice of therapeutic target for the treatment of autoimmune diseases, cancer, and infectious\u0000diseases. Based on the biology of HSP-90, several COOH-terminal ATPase sites of\u0000HSP-90, NH2-terminal ATPase sites of HSP-90, and Histone deacetylase inhibitors are\u0000evaluated and classified under various groups. For the treatment of different inflammatory\u0000disorders, HSP-90 identified as a promising therapeutic target. The present review may guide\u0000researchers for evaluating the HSP-90 targeted pathway as a useful therapeutic target for inflammatory\u0000diseases, including cancers.\u0000","PeriodicalId":10784,"journal":{"name":"Current Chemical Biology","volume":"92 1","pages":"30-37"},"PeriodicalIF":0.0,"publicationDate":"2020-02-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83753580","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 : 2020-01-23DOI: 10.2174/2212796814666200123144645
Sayanti Gupta, C. Pan
Hsp90 chaperone is an encouraging target for the development of novel anticancer agents. The failure of Hsp90 inhibitors to get regulatory approval for the treatment of cancer is hindered due to toxicity, cost involved in their development and formulation issues. The inhibitors against this chaperone is also being evaluated in pre-clinical models for the treatment of diseases other than cancer (Alzheimer, malaria, AIDS, etc.). Recently, Hsp90 inhibitors have shown promising senolytic effect, that is helpful in increasing the health and life span of mice. The senolytic property of Hsp90 inhibitors will make them less toxic for use in humans. The review focuses on Hsp90 inhibitors discovered till date as senolytic agents along with their future prospects. Further, the various models used for the evaluation of senolytic effect are also discussed.
{"title":"Senolytic potential of Hsp90 inhibitors","authors":"Sayanti Gupta, C. Pan","doi":"10.2174/2212796814666200123144645","DOIUrl":"https://doi.org/10.2174/2212796814666200123144645","url":null,"abstract":"\u0000\u0000Hsp90 chaperone is an encouraging target for the development of novel anticancer agents. The failure of Hsp90 inhibitors to get regulatory approval for the treatment of cancer is hindered due to toxicity, cost involved in their development and formulation issues. The inhibitors against this chaperone is also being evaluated in pre-clinical models for the treatment of diseases other than cancer (Alzheimer, malaria, AIDS, etc.). Recently, Hsp90 inhibitors have shown promising senolytic effect, that is helpful in increasing the health and life span of mice. The senolytic property of Hsp90 inhibitors will make them less toxic for use in humans. The review focuses on Hsp90 inhibitors discovered till date as senolytic agents along with their future prospects. Further, the various models used for the evaluation of senolytic effect are also discussed. \u0000","PeriodicalId":10784,"journal":{"name":"Current Chemical Biology","volume":"72 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83730045","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 : 2019-11-30DOI: 10.2174/2212796813666190102102018
Omotuyi I. Olaposi, N. Oyekanmi, Metibemu D. Samuel, Ojochenemi.A Enejoh, Ukwenya Victor, A. Niyi
Takeda G-protein receptor 5 (TGR5) via glucagon-like peptide release and insulin signaling underlies antidiabetic roles of TGR5 agonists. Chromolaena Odorata- derived flavonoid-5,7-dihydroxy-6-4-dimethoxyflavanone (COF) has been identified as (TGR5) agonist. The structural basis for their interaction has not been studied. This study aimed at providing both structural and dynamic insights into COF/TGR5 interaction. Classical GPCR activation signatures (TMIII-TMVI ionic lock, toggle switches, internal water pathway) using classical MD simulation have been used. Y893.29, N933.33 and E1695.43 are key residues found to be involved in ligand binding; the continuous internal water pathway connects hydrophilic groups of the ligand to the TMIII-TMVI interface in COF-bound state, TMIII-TMVI ionic locks ruptures in COF-TGR5 complex but not antagonist-bound state, and ruptured ionic lock is associated with the evolution of active-state “VPVAM” (analogous to “NPxxY”) conformation. Dihedral angles (c2) calculated along the trajectory strongly suggest W2376.48 as a ligand-dependent toggle switch. TGR5 evolves active state conformation from a starting intermediate state conformation when bound to COF, which further supports its underlying anti-diabetic activities.
{"title":"Takeda G-protein Receptor (TGR)-5 Evolves Classical Activestate Conformational Signatures in Complex with Chromolaena Odorata-derived Flavonoid-5,7-dihydroxy-6-4-dimethoxyflavanone","authors":"Omotuyi I. Olaposi, N. Oyekanmi, Metibemu D. Samuel, Ojochenemi.A Enejoh, Ukwenya Victor, A. Niyi","doi":"10.2174/2212796813666190102102018","DOIUrl":"https://doi.org/10.2174/2212796813666190102102018","url":null,"abstract":"\u0000\u0000Takeda G-protein receptor 5 (TGR5) via glucagon-like peptide release\u0000and insulin signaling underlies antidiabetic roles of TGR5 agonists. Chromolaena Odorata-\u0000derived flavonoid-5,7-dihydroxy-6-4-dimethoxyflavanone (COF) has been identified as\u0000(TGR5) agonist. The structural basis for their interaction has not been studied.\u0000\u0000\u0000\u0000This study aimed at providing both structural and dynamic insights into\u0000COF/TGR5 interaction.\u0000\u0000\u0000\u0000Classical GPCR activation signatures (TMIII-TMVI ionic lock, toggle switches,\u0000internal water pathway) using classical MD simulation have been used.\u0000\u0000\u0000\u0000Y893.29, N933.33 and E1695.43 are key residues found to be involved in ligand binding;\u0000the continuous internal water pathway connects hydrophilic groups of the ligand to the\u0000TMIII-TMVI interface in COF-bound state, TMIII-TMVI ionic locks ruptures in COF-TGR5\u0000complex but not antagonist-bound state, and ruptured ionic lock is associated with the evolution\u0000of active-state “VPVAM” (analogous to “NPxxY”) conformation. Dihedral angles (c2)\u0000calculated along the trajectory strongly suggest W2376.48 as a ligand-dependent toggle\u0000switch.\u0000\u0000\u0000\u0000TGR5 evolves active state conformation from a starting intermediate state conformation\u0000when bound to COF, which further supports its underlying anti-diabetic activities.\u0000","PeriodicalId":10784,"journal":{"name":"Current Chemical Biology","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2019-11-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90205256","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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