Pub Date : 2024-01-01DOI: 10.2174/0115680266259174231006070637
Fady Tadros Hakem, Youstina Farid Fouad, Reem K Arafa
Alzheimer's disease (AD) is a neurological disease that affects the memory. AD has been attributed to the aggregations of amyloid-β (Aβ) peptides which result in the formation of plaques that block the neuron-transferring process done by the brain memory cells. These plaques are formed upon cleavage of Amyloid Precursor Protein (APP) by Gamma-Secretase (GS). GS protein has around 141 substrates, the important two are APP and Notch. Considering one of the hot spots in AD research, we focused on GS and its relation to AD. Moreover, a lot of research was done on beta-secretase and drugs were developed to target it however, few drugs are established for GS. GS contains four subunits: Presenilin (PS), PEN-2, Nicastrin, and APH-1. The catalytic subunit is PS, which contains the active site for substrate binding, as well as the allosteric and docking sites. Both PEN-2 and APH-1 are regulators for the stability and activity of GS. Nicastrin, helps the substrates bind to the PS. Additionally, the role of the immuno-protein named "IFITM3" and how it affects the immune system and its relation to AD is presented. GS is one of the most studied proteins with many developed candidates as inhibitors (GSI) and modulators (GSM). Examples of GSI are Semagacestat and Avagacestat while GSM includes E2012; which inhibits the cleavage activity of GS. In this report, each of the four subunits of GS is described in detail, along with the interactions between GS and its inhibitors or modulators. In addition, the FDA-approved drugs are enlisted.
{"title":"Gamma Secretase as an Important Drug Target for Management of Alzheimer's Disease: A Comprehensive Review.","authors":"Fady Tadros Hakem, Youstina Farid Fouad, Reem K Arafa","doi":"10.2174/0115680266259174231006070637","DOIUrl":"10.2174/0115680266259174231006070637","url":null,"abstract":"<p><p>Alzheimer's disease (AD) is a neurological disease that affects the memory. AD has been attributed to the aggregations of amyloid-β (Aβ) peptides which result in the formation of plaques that block the neuron-transferring process done by the brain memory cells. These plaques are formed upon cleavage of Amyloid Precursor Protein (APP) by Gamma-Secretase (GS). GS protein has around 141 substrates, the important two are APP and Notch. Considering one of the hot spots in AD research, we focused on GS and its relation to AD. Moreover, a lot of research was done on beta-secretase and drugs were developed to target it however, few drugs are established for GS. GS contains four subunits: Presenilin (PS), PEN-2, Nicastrin, and APH-1. The catalytic subunit is PS, which contains the active site for substrate binding, as well as the allosteric and docking sites. Both PEN-2 and APH-1 are regulators for the stability and activity of GS. Nicastrin, helps the substrates bind to the PS. Additionally, the role of the immuno-protein named \"IFITM3\" and how it affects the immune system and its relation to AD is presented. GS is one of the most studied proteins with many developed candidates as inhibitors (GSI) and modulators (GSM). Examples of GSI are Semagacestat and Avagacestat while GSM includes E2012; which inhibits the cleavage activity of GS. In this report, each of the four subunits of GS is described in detail, along with the interactions between GS and its inhibitors or modulators. In addition, the FDA-approved drugs are enlisted.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41194376","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 : 2024-01-01DOI: 10.2174/0115680266256963230921061925
Dayanna Orosco, Arturo René Mendoza, Carlos Mario Meléndez
Recent developments in the use of natural product-based molecules as antiparasitic agents for Malaria, leishmaniasis (LE), Chagas disease (CD), and Human African trypanosomiasis (HAT) are reviewed. The role of diverse plants in developing bioactive species is discussed in addition to analyzing the structural diversity of natural products as active agents and the diverse biological applications in CD, HAT, LE, and Malaria. This review focuses on medicinal chemistry, emphasizing the structural characteristics of natural molecules as bioactive agents against parasitic infections caused by Leishmania, Trypanosoma, and Plasmodium parasites.
{"title":"Exploring the Potential of Natural Products as Antiparasitic Agents for Neglected Tropical Diseases.","authors":"Dayanna Orosco, Arturo René Mendoza, Carlos Mario Meléndez","doi":"10.2174/0115680266256963230921061925","DOIUrl":"10.2174/0115680266256963230921061925","url":null,"abstract":"<p><p>Recent developments in the use of natural product-based molecules as antiparasitic agents for Malaria, leishmaniasis (LE), Chagas disease (CD), and Human African trypanosomiasis (HAT) are reviewed. The role of diverse plants in developing bioactive species is discussed in addition to analyzing the structural diversity of natural products as active agents and the diverse biological applications in CD, HAT, LE, and Malaria. This review focuses on medicinal chemistry, emphasizing the structural characteristics of natural molecules as bioactive agents against parasitic infections caused by <i>Leishmania, Trypanosoma</i>, and <i>Plasmodium parasites</i>.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41233180","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 : 2024-01-01DOI: 10.2174/1568026623666230914104141
Manzoor Hussain, Rakesh Kr Thakur, Jabeena Khazir, Sajad Ahmed, Mohammad Imtiyaj Khan, Praveen Rahi, Latif Ahmad Peer, Pragadheesh Vppalayam Shanmugam, Satwinderjeet Kaur, Soom Nath Raina, Zafar Ahmad Reshi, Deepmala Sehgal, Vijay Rani Rajpal, Bilal Ahmad Mir
Biologically active secondary metabolites, essential oils, and volatile compounds derived from medicinal and aromatic plants play a crucial role in promoting human health. Within the large family Asteraceae, the genus Artemisia consists of approximately 500 species. Artemisia species have a rich history in traditional medicine worldwide, offering remedies for a wide range of ailments, such as malaria, jaundice, toothache, gastrointestinal problems, wounds, inflammatory diseases, diarrhoea, menstrual pains, skin disorders, headache, and intestinal parasites. The therapeutic potential of Artemisia species is derived from a multitude of phytoconstituents, including terpenoids, phenols, flavonoids, coumarins, sesquiterpene lactones, lignans, and alkaloids that serve as active pharmaceutical ingredients (API). The remarkable antimalarial, antimicrobial, anthelmintic, antidiabetic, anti-inflammatory, anticancer, antispasmodic, antioxidative and insecticidal properties possessed by the species are attributed to these APIs. Interestingly, several commercially utilized pharmaceutical drugs, including arglabin, artemisinin, artemether, artesunate, santonin, and tarralin have also been derived from different Artemisia species. However, despite the vast medicinal potential, only a limited number of Artemisia species have been exploited commercially. Further, the available literature on traditional and pharmacological uses of Artemisia lacks comprehensive reviews. Therefore, there is an urgent need to bridge the existing knowledge gaps and provide a scientific foundation for future Artemisia research endeavours. It is in this context, the present review aims to provide a comprehensive account of the traditional uses, phytochemistry, documented biological properties and toxicity of all the species of Artemisia and offers useful insights for practitioners and researchers into underutilized species and their potential applications. This review aims to stimulate further exploration, experimentation and collaboration to fully realize the therapeutic potential of Artemisia in augmenting human health and well-being.
{"title":"Traditional uses, Phytochemistry, Pharmacology, and Toxicology of the Genus <i>Artemisia L. (Asteraceae)</i>: A High-value Medicinal Plant.","authors":"Manzoor Hussain, Rakesh Kr Thakur, Jabeena Khazir, Sajad Ahmed, Mohammad Imtiyaj Khan, Praveen Rahi, Latif Ahmad Peer, Pragadheesh Vppalayam Shanmugam, Satwinderjeet Kaur, Soom Nath Raina, Zafar Ahmad Reshi, Deepmala Sehgal, Vijay Rani Rajpal, Bilal Ahmad Mir","doi":"10.2174/1568026623666230914104141","DOIUrl":"10.2174/1568026623666230914104141","url":null,"abstract":"<p><p>Biologically active secondary metabolites, essential oils, and volatile compounds derived from medicinal and aromatic plants play a crucial role in promoting human health. Within the large family Asteraceae, the genus <i>Artemisia</i> consists of approximately 500 species. <i>Artemisia</i> species have a rich history in traditional medicine worldwide, offering remedies for a wide range of ailments, such as malaria, jaundice, toothache, gastrointestinal problems, wounds, inflammatory diseases, diarrhoea, menstrual pains, skin disorders, headache, and intestinal parasites. The therapeutic potential of <i>Artemisia</i> species is derived from a multitude of phytoconstituents, including terpenoids, phenols, flavonoids, coumarins, sesquiterpene lactones, lignans, and alkaloids that serve as active pharmaceutical ingredients (API). The remarkable antimalarial, antimicrobial, anthelmintic, antidiabetic, anti-inflammatory, anticancer, antispasmodic, antioxidative and insecticidal properties possessed by the species are attributed to these APIs. Interestingly, several commercially utilized pharmaceutical drugs, including arglabin, artemisinin, artemether, artesunate, santonin, and tarralin have also been derived from different <i>Artemisia</i> species. However, despite the vast medicinal potential, only a limited number of <i>Artemisia</i> species have been exploited commercially. Further, the available literature on traditional and pharmacological uses of <i>Artemisia</i> lacks comprehensive reviews. Therefore, there is an urgent need to bridge the existing knowledge gaps and provide a scientific foundation for future <i>Artemisia</i> research endeavours. It is in this context, the present review aims to provide a comprehensive account of the traditional uses, phytochemistry, documented biological properties and toxicity of all the species of <i>Artemisia</i> and offers useful insights for practitioners and researchers into underutilized species and their potential applications. This review aims to stimulate further exploration, experimentation and collaboration to fully realize the therapeutic potential of <i>Artemisia</i> in augmenting human health and well-being.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10241750","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 : 2024-01-01DOI: 10.2174/0115680266289898240322073258
Yasemin Budama-Kilinc, Ozan Baris Kurtur, Bahar Gok, Nisanur Cakmakci, Serda Kecel-Gunduz, Necdet Mehmet Unel, Taylan Kurtulus Ozturk
Respiratory viruses have caused many pandemics from past to present and are among the top global public health problems due to their rate of spread. The recently experienced COVID-19 pandemic has led to an understanding of the importance of rapid diagnostic tests to prevent epidemics and the difficulties of developing new vaccines. On the other hand, the emergence of resistance to existing antiviral drugs during the treatment process poses a major problem for society and global health systems. Therefore, there is a need for new approaches for the diagnosis, prophylaxis, and treatment of existing or new types of respiratory viruses. Immunoglobulin Y antibodies (IgYs) obtained from the yolk of poultry eggs have significant advantages, such as high production volumes, low production costs, and high selectivity, which enable the development of innovative and strategic products. Especially in diagnosing respiratory viruses, antibody-based biosensors in which these antibodies are integrated have the potential to provide superiority in making rapid and accurate diagnosis as a practical diagnostic tool. This review article aims to provide information on using IgY antibodies in diagnostic, prophylactic, and therapeutic applications for respiratory viruses and to provide a perspective for future innovative applications.
从古至今,呼吸道病毒已造成多次大流行,并因其传播速度快而成为全球公共卫生的首要问题之一。最近发生的 COVID-19 大流行使人们认识到快速诊断检测对预防流行病的重要性以及开发新疫苗的困难。另一方面,在治疗过程中出现的对现有抗病毒药物的抗药性也给社会和全球卫生系统带来了重大问题。因此,需要新的方法来诊断、预防和治疗现有或新型呼吸道病毒。从禽蛋蛋黄中提取的免疫球蛋白 Y 抗体(IgYs)具有产量高、生产成本低、选择性强等显著优势,可用于开发创新型战略产品。特别是在诊断呼吸道病毒方面,集成了这些抗体的基于抗体的生物传感器有可能作为一种实用的诊断工具,在快速准确诊断方面提供优越性。这篇综述文章旨在介绍 IgY 抗体在呼吸道病毒诊断、预防和治疗中的应用,并为未来的创新应用提供展望。
{"title":"Use of Immunoglobulin Y Antibodies: Biosensor-based Diagnostic Systems and Prophylactic and Therapeutic Drug Delivery Systems for Viral Respiratory Diseases.","authors":"Yasemin Budama-Kilinc, Ozan Baris Kurtur, Bahar Gok, Nisanur Cakmakci, Serda Kecel-Gunduz, Necdet Mehmet Unel, Taylan Kurtulus Ozturk","doi":"10.2174/0115680266289898240322073258","DOIUrl":"10.2174/0115680266289898240322073258","url":null,"abstract":"<p><p>Respiratory viruses have caused many pandemics from past to present and are among the top global public health problems due to their rate of spread. The recently experienced COVID-19 pandemic has led to an understanding of the importance of rapid diagnostic tests to prevent epidemics and the difficulties of developing new vaccines. On the other hand, the emergence of resistance to existing antiviral drugs during the treatment process poses a major problem for society and global health systems. Therefore, there is a need for new approaches for the diagnosis, prophylaxis, and treatment of existing or new types of respiratory viruses. Immunoglobulin Y antibodies (IgYs) obtained from the yolk of poultry eggs have significant advantages, such as high production volumes, low production costs, and high selectivity, which enable the development of innovative and strategic products. Especially in diagnosing respiratory viruses, antibody-based biosensors in which these antibodies are integrated have the potential to provide superiority in making rapid and accurate diagnosis as a practical diagnostic tool. This review article aims to provide information on using IgY antibodies in diagnostic, prophylactic, and therapeutic applications for respiratory viruses and to provide a perspective for future innovative applications.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140335116","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 : 2024-01-01DOI: 10.2174/0115680266293173240506054439
Seyed Morteza Naghib, Bahar Ahmadi, M R Mozafari
Chitosan-based nanoparticles have emerged as a promising tool in the realm of cancer therapy, particularly for gene delivery. With cancer being a prevalent and devastating disease, finding effective treatment options is of utmost importance. These nanoparticles provide a unique solution by encapsulating specific genes and delivering them directly to cancer cells, offering immense potential for targeted therapy. The biocompatibility and biodegradability of chitosan, a naturally derived polymer, make it an ideal candidate for this purpose. The nanoparticles protect the genetic material during transportation and enhance its cellular uptake, ensuring effective delivery to the site of action. Furthermore, the unique properties of chitosan-based nanoparticles allow for the controlled release of genes, maximizing their therapeutic effect while minimizing adverse effects. By advancing the field of gene therapy through the use of chitosan-based nanoparticles, scientists are making significant strides toward more humane and personalized treatments for cancer patients.
{"title":"Stimuli-sensitive Chitosan-based Nanosystems-immobilized Nucleic Acids for Gene Therapy in Breast Cancer and Hepatocellular Carcinoma.","authors":"Seyed Morteza Naghib, Bahar Ahmadi, M R Mozafari","doi":"10.2174/0115680266293173240506054439","DOIUrl":"10.2174/0115680266293173240506054439","url":null,"abstract":"<p><p>Chitosan-based nanoparticles have emerged as a promising tool in the realm of cancer therapy, particularly for gene delivery. With cancer being a prevalent and devastating disease, finding effective treatment options is of utmost importance. These nanoparticles provide a unique solution by encapsulating specific genes and delivering them directly to cancer cells, offering immense potential for targeted therapy. The biocompatibility and biodegradability of chitosan, a naturally derived polymer, make it an ideal candidate for this purpose. The nanoparticles protect the genetic material during transportation and enhance its cellular uptake, ensuring effective delivery to the site of action. Furthermore, the unique properties of chitosan-based nanoparticles allow for the controlled release of genes, maximizing their therapeutic effect while minimizing adverse effects. By advancing the field of gene therapy through the use of chitosan-based nanoparticles, scientists are making significant strides toward more humane and personalized treatments for cancer patients.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140944491","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 : 2024-01-01DOI: 10.2174/1568026623666230829152150
Valerio Ricci, Domenico de Berardis, Giovanni Martinotti, Giuseppe Maina
Background: Cannabis is the most widely used illicit substance. Numerous scientific evidence confirm the strong association between cannabis and psychosis. Exposure to cannabis can induce the development of psychosis and schizophrenia in vulnerable individuals. However, the neurobiological processes underlying this relationship are unknown. Neurotrophins are a class of proteins that serve as survival factors for central nervous system (CNS) neurons. In particular, Nerve Growth Factor (NGF) plays an important role in the survival and function of cholinergic neurons while Brain Derived Neurotrophic Factor (BDNF) is involved in synaptic plasticity and the maintenance of midbrain dopaminergic and cholinergic neurons. Glial Cell Derived Neurotrophic Factor (GDNF) promotes the survival of midbrain dopaminergic neurons and Neuregulin 1 (NrG- 1) contributes to glutamatergic signals regulating the N-methyl-D-aspartate (NMDA). They have a remarkable influence on the neurons involved in the Δ-9-THC (tethra-hydro-cannabinol) action, such as dopaminergic and glutamatergic neurons, and can play dual roles: first, in neuronal survival and death, and, second, in activity-dependent plasticity.
Methods: In this brief update, reviewing in a narrative way the relevant literature, we will focus on the effects of cannabis on this class of proteins, which may be implicated, at least in part, in the mechanism of the psychostimulant-induced neurotoxicity and psychosis.
Conclusion: Since altered levels of neurotrophins may participate in the pathogenesis of psychotic disorders which are common in drug users, one possible hypothesis is that repeated cannabis exposure can cause psychosis by interfering with neurotrophins synthesis and utilization by CNS neurons.
{"title":"Neurotrophic Factors in Cannabis-induced Psychosis: An Update.","authors":"Valerio Ricci, Domenico de Berardis, Giovanni Martinotti, Giuseppe Maina","doi":"10.2174/1568026623666230829152150","DOIUrl":"10.2174/1568026623666230829152150","url":null,"abstract":"<p><strong>Background: </strong>Cannabis is the most widely used illicit substance. Numerous scientific evidence confirm the strong association between cannabis and psychosis. Exposure to cannabis can induce the development of psychosis and schizophrenia in vulnerable individuals. However, the neurobiological processes underlying this relationship are unknown. Neurotrophins are a class of proteins that serve as survival factors for central nervous system (CNS) neurons. In particular, Nerve Growth Factor (NGF) plays an important role in the survival and function of cholinergic neurons while Brain Derived Neurotrophic Factor (BDNF) is involved in synaptic plasticity and the maintenance of midbrain dopaminergic and cholinergic neurons. Glial Cell Derived Neurotrophic Factor (GDNF) promotes the survival of midbrain dopaminergic neurons and Neuregulin 1 (NrG- 1) contributes to glutamatergic signals regulating the N-methyl-D-aspartate (NMDA). They have a remarkable influence on the neurons involved in the Δ-9-THC (tethra-hydro-cannabinol) action, such as dopaminergic and glutamatergic neurons, and can play dual roles: first, in neuronal survival and death, and, second, in activity-dependent plasticity.</p><p><strong>Methods: </strong>In this brief update, reviewing in a narrative way the relevant literature, we will focus on the effects of cannabis on this class of proteins, which may be implicated, at least in part, in the mechanism of the psychostimulant-induced neurotoxicity and psychosis.</p><p><strong>Conclusion: </strong>Since altered levels of neurotrophins may participate in the pathogenesis of psychotic disorders which are common in drug users, one possible hypothesis is that repeated cannabis exposure can cause psychosis by interfering with neurotrophins synthesis and utilization by CNS neurons.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10167657","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 : 2024-01-01DOI: 10.2174/0115680266315388240801053401
Sayonara Maria Calado Gonçalves, Lília Vieira Galdino, Morganna Costa Lima, José Arion da Silva Moura, Douglas Carvalho Francisco Viana, Michelle Melgarejo da Rosa, Luiz Felipe Gomes Rebello Ferreira, Marcelo Zaldini Hernandes, Michelly Cristiny Pereira, Moacyr Jesus Barreto de Melo Rêgo, Ivan da Rocha Pitta, Rafael de Oliveira França, Marina Galdino da Rocha Pitta, Maira Galdino da Rocha Pitta
Objective: In this study, we have synthesized 19 Thiazolidine (TZD) derivatives to investigate their potential anti-ZIKV effects.
Methods: Nineteen thiazolidine derivatives were synthesized and evaluated for their cytotoxicity and antiviral activity against the ZIKA virus.
Results: Among them, six demonstrated remarkable selectivity against the ZIKV virus, exhibiting IC50 values of <5μM, and the other compounds did not demonstrate selectivity for the virus. Interestingly, several derivatives effectively suppressed the replication of ZIKV RNA copies, with derivatives significantly reducing ZIKV mRNA levels at 24 hours post-infection (hpi). Notably, two derivatives (ZKC-4 and -9) stood out by demonstrating a protective effect against ZIKV cell entry. Informed by computational analysis of binding affinity and intermolecular interactions within the NS5 domain's N-7 and O'2 positions, ZKC-4 and FT-39 displayed the highest predicted affinities. Intriguingly, ZKC-4 and ZKC-9 derivatives exhibited the most favorable predicted binding affinities for the ZIKV-E binding site.
Conclusion: The significance of TZDs as potent antiviral agents is underscored by these findings, suggesting that exploring TZD derivatives holds promise for advancing antiviral therapeutic strategies.
{"title":"Evaluation of Thiazolidine Derivatives with Potential Anti-ZIKV Activity.","authors":"Sayonara Maria Calado Gonçalves, Lília Vieira Galdino, Morganna Costa Lima, José Arion da Silva Moura, Douglas Carvalho Francisco Viana, Michelle Melgarejo da Rosa, Luiz Felipe Gomes Rebello Ferreira, Marcelo Zaldini Hernandes, Michelly Cristiny Pereira, Moacyr Jesus Barreto de Melo Rêgo, Ivan da Rocha Pitta, Rafael de Oliveira França, Marina Galdino da Rocha Pitta, Maira Galdino da Rocha Pitta","doi":"10.2174/0115680266315388240801053401","DOIUrl":"10.2174/0115680266315388240801053401","url":null,"abstract":"<p><strong>Objective: </strong>In this study, we have synthesized 19 Thiazolidine (TZD) derivatives to investigate their potential anti-ZIKV effects.</p><p><strong>Methods: </strong>Nineteen thiazolidine derivatives were synthesized and evaluated for their cytotoxicity and antiviral activity against the ZIKA virus.</p><p><strong>Results: </strong>Among them, six demonstrated remarkable selectivity against the ZIKV virus, exhibiting IC50 values of <5μM, and the other compounds did not demonstrate selectivity for the virus. Interestingly, several derivatives effectively suppressed the replication of ZIKV RNA copies, with derivatives significantly reducing ZIKV mRNA levels at 24 hours post-infection (hpi). Notably, two derivatives (ZKC-4 and -9) stood out by demonstrating a protective effect against ZIKV cell entry. Informed by computational analysis of binding affinity and intermolecular interactions within the NS5 domain's N-7 and O'2 positions, ZKC-4 and FT-39 displayed the highest predicted affinities. Intriguingly, ZKC-4 and ZKC-9 derivatives exhibited the most favorable predicted binding affinities for the ZIKV-E binding site.</p><p><strong>Conclusion: </strong>The significance of TZDs as potent antiviral agents is underscored by these findings, suggesting that exploring TZD derivatives holds promise for advancing antiviral therapeutic strategies.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":2.9,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141970849","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}
The Hedgehog (Hh) signaling pathway plays a crucial role in diverse biological processes such as cell differentiation, proliferation, senescence, tumorigenesis, malignant transformation, and drug resistance. Aberrant Hh signaling, resulting from mutations and excessive activation, can contribute to the development of various diseases during different stages of biogenesis and development. Moreover, it has been linked to unfavorable outcomes in several human cancers, including basal cell carcinoma (BCC), multiple myeloma (MM), melanoma, and breast cancer. Hence, the presence of mutations and excessive activation of the Hh pathway presents obstacles and constraints in the realm of cancer treatment. Extant research has demonstrated that small molecule inhibitors are regarded as the most effective therapeutic approaches for targeting the Hh pathway in contrast to traditional chemotherapy and radiotherapy. Consequently, this review focuses on the present repertoire of small molecule inhibitors that target various components of the Hh pathway, including Hh ligands, Ptch receptors, Smo transmembrane proteins, and Gli nuclear transcription factors. This study provides a comprehensive analysis of small molecules' structural and functional aspects in the preclinical and clinical management of cancer. Additionally, it elucidates the obstacles encountered in targeting the Hh pathway for human cancer therapy and proposes potential therapeutic approaches.
{"title":"Current Status of Hedgehog Signaling Inhibitors.","authors":"Xiaotang Wang, Tian Wang, Xiaona Song, Jiping Gao, Guoqiang Xu, Yunhui Ma, Guohua Song","doi":"10.2174/0115680266280850231221074340","DOIUrl":"10.2174/0115680266280850231221074340","url":null,"abstract":"<p><p>The Hedgehog (Hh) signaling pathway plays a crucial role in diverse biological processes such as cell differentiation, proliferation, senescence, tumorigenesis, malignant transformation, and drug resistance. Aberrant Hh signaling, resulting from mutations and excessive activation, can contribute to the development of various diseases during different stages of biogenesis and development. Moreover, it has been linked to unfavorable outcomes in several human cancers, including basal cell carcinoma (BCC), multiple myeloma (MM), melanoma, and breast cancer. Hence, the presence of mutations and excessive activation of the Hh pathway presents obstacles and constraints in the realm of cancer treatment. Extant research has demonstrated that small molecule inhibitors are regarded as the most effective therapeutic approaches for targeting the Hh pathway in contrast to traditional chemotherapy and radiotherapy. Consequently, this review focuses on the present repertoire of small molecule inhibitors that target various components of the Hh pathway, including Hh ligands, Ptch receptors, Smo transmembrane proteins, and Gli nuclear transcription factors. This study provides a comprehensive analysis of small molecules' structural and functional aspects in the preclinical and clinical management of cancer. Additionally, it elucidates the obstacles encountered in targeting the Hh pathway for human cancer therapy and proposes potential therapeutic approaches.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139477530","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: DNA methyltransferases (DNMTs) have been reported to be potential drug targets in various cancers. The major hurdle in inhibiting DNMTs is the lack of knowledge about different DNMTs and their role in the hypermethylation of gene promoters in cancer cells. Lack of information on specificity, stability, and higher toxicity of previously reported DNMT inhibitors is the major reason for inadequate epigenetic cancer therapy. DNMT1 and DNMT3A are the two DNMTs that are majorly overexpressed in cancers.
Objective: In this study, we have presented computational and experimental analyses of the potential of some natural compounds, withaferin A (Wi-A), withanone (Wi-N), and caffeic acid phenethyl ester (CAPE), as DNMT inhibitors, in comparison to sinefungin (SFG), a known dual inhibitor of DNMT1 and DNMT3A.
Methods: We used classical simulation methods, such as molecular docking and molecular dynamics simulations, to investigate the binding potential and properties of the test compounds with DNMT1 and DNMT3A. Cell culture-based assays were used to investigate the inactivation of DNMTs and the resulting hypomethylation of the p16INK4A promoter, a key tumour suppressor that is inactivated by hypermethylation in cancer cells, resulting in upregulation of its expression.
Results: Among the three test compounds (Wi-A, Wi-N, and CAPE), Wi-A showed the highest binding affinity to both DNMT1 and DNMT3A; CAPE showed the highest affinity to DNMT3A, and Wi-N showed a moderate affinity interaction with both. The binding energies of Wi-A and CAPE were further compared with SFG. Expression analysis of DNMTs showed no difference between control and treated cells. Cell viability and p16INK4A expression analysis showed a dose-dependent decrease in viability, an increase in p16INK4A, and a stronger effect of Wi-A compared to Wi-N and CAPE.
Conclusion: The study demonstrated the differential binding ability of Wi-A, Wi-N, and CAPE to DNMT1 and DNMT3A, which was associated with their inactivation, leading to hypomethylation and desilencing of the p16INK4A tumour suppressor in cancer cells. The test compounds, particularly Wi-A, have the potential for cancer therapy.
{"title":"Effect of Withaferin-A, Withanone, and Caffeic Acid Phenethyl Ester on DNA Methyltransferases: Potential in Epigenetic Cancer Therapy.","authors":"Vipul Kumar, Jaspreet Kaur Dhanjal, Anissa Nofita Sari, Mallika Khurana, Sunil C Kaul, Renu Wadhwa, Durai Sundar","doi":"10.2174/1568026623666230726105017","DOIUrl":"10.2174/1568026623666230726105017","url":null,"abstract":"<p><strong>Background: </strong>DNA methyltransferases (DNMTs) have been reported to be potential drug targets in various cancers. The major hurdle in inhibiting DNMTs is the lack of knowledge about different DNMTs and their role in the hypermethylation of gene promoters in cancer cells. Lack of information on specificity, stability, and higher toxicity of previously reported DNMT inhibitors is the major reason for inadequate epigenetic cancer therapy. DNMT1 and DNMT3A are the two DNMTs that are majorly overexpressed in cancers.</p><p><strong>Objective: </strong>In this study, we have presented computational and experimental analyses of the potential of some natural compounds, withaferin A (Wi-A), withanone (Wi-N), and caffeic acid phenethyl ester (CAPE), as DNMT inhibitors, in comparison to sinefungin (SFG), a known dual inhibitor of DNMT1 and DNMT3A.</p><p><strong>Methods: </strong>We used classical simulation methods, such as molecular docking and molecular dynamics simulations, to investigate the binding potential and properties of the test compounds with DNMT1 and DNMT3A. Cell culture-based assays were used to investigate the inactivation of DNMTs and the resulting hypomethylation of the p16<sup>INK4A</sup> promoter, a key tumour suppressor that is inactivated by hypermethylation in cancer cells, resulting in upregulation of its expression.</p><p><strong>Results: </strong>Among the three test compounds (Wi-A, Wi-N, and CAPE), Wi-A showed the highest binding affinity to both DNMT1 and DNMT3A; CAPE showed the highest affinity to DNMT3A, and Wi-N showed a moderate affinity interaction with both. The binding energies of Wi-A and CAPE were further compared with SFG. Expression analysis of DNMTs showed no difference between control and treated cells. Cell viability and p16<sup>INK4A</sup> expression analysis showed a dose-dependent decrease in viability, an increase in p16<sup>INK4A</sup>, and a stronger effect of Wi-A compared to Wi-N and CAPE.</p><p><strong>Conclusion: </strong>The study demonstrated the differential binding ability of Wi-A, Wi-N, and CAPE to DNMT1 and DNMT3A, which was associated with their inactivation, leading to hypomethylation and desilencing of the p16<sup>INK4A</sup> tumour suppressor in cancer cells. The test compounds, particularly Wi-A, have the potential for cancer therapy.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9879248","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 : 2024-01-01DOI: 10.2174/0115680266282179240124072121
Kavya Singh, Navjeet Kaur, Ashish Prabhu
Background: SARS-CoV-2, the unique coronavirus that causes COVID-19, has wreaked damage around the globe, with victims displaying a wide range of difficulties that have encouraged medical professionals to look for innovative technical solutions and therapeutic approaches. Artificial intelligence-based methods have contributed a significant part in tackling complicated issues, and some institutions have been quick to embrace and tailor these solutions in response to the COVID-19 pandemic's obstacles. Here, in this review article, we have covered a few DL techniques for COVID-19 detection and diagnosis, as well as ML techniques for COVID-19 identification, severity classification, vaccine and drug development, mortality rate prediction, contact tracing, risk assessment, and public distancing. This review illustrates the overall impact of AI/ML tools on tackling and managing the outbreak.
Purpose: The focus of this research was to undertake a thorough evaluation of the literature on the part of Artificial Intelligence (AI) as a complete and efficient solution in the battle against the COVID-19 epidemic in the domains of detection and diagnostics of disease, mortality prediction and vaccine as well as drug development.
Methods: A comprehensive exploration of PubMed, Web of Science, and Science Direct was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) regulations to find all possibly suitable papers conducted and made publicly available between December 1, 2019, and August 2023. COVID-19, along with AI-specific words, was used to create the query syntax.
Results: During the period covered by the search strategy, 961 articles were published and released online. Out of these, a total of 135 papers were chosen for additional investigation. Mortality rate prediction, early detection and diagnosis, vaccine as well as drug development, and lastly, incorporation of AI for supervising and controlling the COVID-19 pandemic were the four main topics focused entirely on AI applications used to tackle the COVID-19 crisis. Out of 135, 60 research papers focused on the detection and diagnosis of the COVID-19 pandemic. Next, 19 of the 135 studies applied a machine-learning approach for mortality rate prediction. Another 22 research publications emphasized the vaccine as well as drug development. Finally, the remaining studies were concentrated on controlling the COVID-19 pandemic by applying AI AI-based approach to it.
Conclusion: We compiled papers from the available COVID-19 literature that used AI-based methodologies to impart insights into various COVID-19 topics in this comprehensive study. Our results suggest crucial characteristics, data types, and COVID-19 tools that can aid in medical and translational research facilitation.
{"title":"Combating COVID-19 Crisis using Artificial Intelligence (AI) Based Approach: Systematic Review.","authors":"Kavya Singh, Navjeet Kaur, Ashish Prabhu","doi":"10.2174/0115680266282179240124072121","DOIUrl":"10.2174/0115680266282179240124072121","url":null,"abstract":"<p><strong>Background: </strong>SARS-CoV-2, the unique coronavirus that causes COVID-19, has wreaked damage around the globe, with victims displaying a wide range of difficulties that have encouraged medical professionals to look for innovative technical solutions and therapeutic approaches. Artificial intelligence-based methods have contributed a significant part in tackling complicated issues, and some institutions have been quick to embrace and tailor these solutions in response to the COVID-19 pandemic's obstacles. Here, in this review article, we have covered a few DL techniques for COVID-19 detection and diagnosis, as well as ML techniques for COVID-19 identification, severity classification, vaccine and drug development, mortality rate prediction, contact tracing, risk assessment, and public distancing. This review illustrates the overall impact of AI/ML tools on tackling and managing the outbreak.</p><p><strong>Purpose: </strong>The focus of this research was to undertake a thorough evaluation of the literature on the part of Artificial Intelligence (AI) as a complete and efficient solution in the battle against the COVID-19 epidemic in the domains of detection and diagnostics of disease, mortality prediction and vaccine as well as drug development.</p><p><strong>Methods: </strong>A comprehensive exploration of PubMed, Web of Science, and Science Direct was conducted using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) regulations to find all possibly suitable papers conducted and made publicly available between December 1, 2019, and August 2023. COVID-19, along with AI-specific words, was used to create the query syntax.</p><p><strong>Results: </strong>During the period covered by the search strategy, 961 articles were published and released online. Out of these, a total of 135 papers were chosen for additional investigation. Mortality rate prediction, early detection and diagnosis, vaccine as well as drug development, and lastly, incorporation of AI for supervising and controlling the COVID-19 pandemic were the four main topics focused entirely on AI applications used to tackle the COVID-19 crisis. Out of 135, 60 research papers focused on the detection and diagnosis of the COVID-19 pandemic. Next, 19 of the 135 studies applied a machine-learning approach for mortality rate prediction. Another 22 research publications emphasized the vaccine as well as drug development. Finally, the remaining studies were concentrated on controlling the COVID-19 pandemic by applying AI AI-based approach to it.</p><p><strong>Conclusion: </strong>We compiled papers from the available COVID-19 literature that used AI-based methodologies to impart insights into various COVID-19 topics in this comprehensive study. Our results suggest crucial characteristics, data types, and COVID-19 tools that can aid in medical and translational research facilitation.</p>","PeriodicalId":11076,"journal":{"name":"Current topics in medicinal chemistry","volume":null,"pages":null},"PeriodicalIF":3.4,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691468","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}