Pub Date : 2023-07-13DOI: 10.2174/1570180820666230713112757
Shubham Kumar, Jasmeen Handa, B. Kumari, Samir Negi, Pinky Arora
Alzheimer’s disease is the most prevalent disease in elderly population. AChE inhibitors can be employed in order to treat this condition. Several AChE inhibitor molecules are approved by the US FDA for the treatment of Alzheimer’s disease. AChE inhibitors were designed with the aim to search for new potential therapeutic molecules with lesser side effects. The molecular structures were created using ChemBiodraw Ultra, and the software AutoDock Vina 1.5.6 was used to conduct the docking study. Online prediction of log p was made using SwissADME. The maximum binding affinity was shown by JH14 molecule against AChE receptor, among all the designed molecules. The lipophilic properties of the best binding molecules were also determined using LogP values, which reveal LogP in the range of 3.39-3.66 for good absorption and elimination. AChE inhibitors were designed which resulted in new lead molecules with higher binding affinity and better pharmacokinetics profile.
{"title":"Utilization of computational tools for discovery of reticuline based derivatives as AChES inhibitors to treat Alzheimer’s disease","authors":"Shubham Kumar, Jasmeen Handa, B. Kumari, Samir Negi, Pinky Arora","doi":"10.2174/1570180820666230713112757","DOIUrl":"https://doi.org/10.2174/1570180820666230713112757","url":null,"abstract":"\u0000\u0000Alzheimer’s disease is the most prevalent disease in elderly population. AChE inhibitors can be employed in order to treat this condition. Several AChE inhibitor molecules are approved by the US FDA for the treatment of Alzheimer’s disease.\u0000\u0000\u0000\u0000AChE inhibitors were designed with the aim to search for new potential therapeutic molecules with lesser side effects.\u0000\u0000\u0000\u0000The molecular structures were created using ChemBiodraw Ultra, and the software AutoDock Vina 1.5.6 was used to conduct the docking study. Online prediction of log p was made using SwissADME.\u0000\u0000\u0000\u0000The maximum binding affinity was shown by JH14 molecule against AChE receptor, among all the designed molecules. The lipophilic properties of the best binding molecules were also determined using LogP values, which reveal LogP in the range of 3.39-3.66 for good absorption and elimination.\u0000\u0000\u0000\u0000AChE inhibitors were designed which resulted in new lead molecules with higher binding affinity and better pharmacokinetics profile.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77856705","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-12DOI: 10.2174/1570180820666230712104959
Abhishek Pathak, S. P. Singh, A. Prakash, A. Tiwari
Altered metabolism is a significant characteristic of cancer, with malignant cells exhibiting elevated levels of enzymes involved in bioenergetic and biosynthetic processes. Targeting metabolic enzymes has become a key approach in anticancer therapy, leading to the discovery of metabolic inhibitors such as 3-bromopyruvate (3-BP) with broad anticancer activity. Novel therapeutics are needed to treat and prevent this fatal disease, and natural substances are gaining attention as potentially safer alternatives to conventional therapies like chemotherapy. This study aimed to identify novel drug-like molecules for anticancer treatment using an in-silico approach. Twenty-eight phytocompounds from Cichorium intybus were selected for molecular docking against target enzymes involved in the TCA and glycolysis cycles and compared with 3-BP, a standard broad-spectrum anticancer drug, using Maestro (Schrodinger software). Comparison of docking scores revealed that the phytoconstituents of Cichorium intybus exhibited stronger binding to metabolic enzymes compared to 3-BP. Additionally, drug-likeness analysis using the admetSAR and Lipinski filter indicated that most of the selected phytoconstituents and 3-BP demonstrated desirable criteria as anticancer drugs. Conclusion This research offers insightful information about molecular interactions between phytoconstituents of Cichorium intybus, 3-BP, and metabolic enzymes. These findings may contribute to the development and optimization of therapeutic approaches against cancer, utilizing these phytoconstituents as ligands.
{"title":"Designing of Anticancer Therapeutical Strategies: Implications of Molecular Docking Studies of Phytochemicals of Cichorium Intybus to Metabolic Regulatory Enzymes","authors":"Abhishek Pathak, S. P. Singh, A. Prakash, A. Tiwari","doi":"10.2174/1570180820666230712104959","DOIUrl":"https://doi.org/10.2174/1570180820666230712104959","url":null,"abstract":"\u0000\u0000Altered metabolism is a significant characteristic of cancer, with malignant cells exhibiting elevated levels of enzymes involved in bioenergetic and biosynthetic processes. Targeting metabolic enzymes has become a key approach in anticancer therapy, leading to the discovery of metabolic inhibitors such as 3-bromopyruvate (3-BP) with broad anticancer activity. Novel therapeutics are needed to treat and prevent this fatal disease, and natural substances are gaining attention as potentially safer alternatives to conventional therapies like chemotherapy.\u0000\u0000\u0000\u0000This study aimed to identify novel drug-like molecules for anticancer treatment using an in-silico approach. Twenty-eight phytocompounds from Cichorium intybus were selected for molecular docking against target enzymes involved in the TCA and glycolysis cycles and compared with 3-BP, a standard broad-spectrum anticancer drug, using Maestro (Schrodinger software).\u0000\u0000\u0000\u0000Comparison of docking scores revealed that the phytoconstituents of Cichorium intybus exhibited stronger binding to metabolic enzymes compared to 3-BP. Additionally, drug-likeness analysis using the admetSAR and Lipinski filter indicated that most of the selected phytoconstituents and 3-BP demonstrated desirable criteria as anticancer drugs.\u0000\u0000\u0000\u0000Conclusion\u0000This research offers insightful information about molecular interactions between phytoconstituents of Cichorium intybus, 3-BP, and metabolic enzymes. These findings may contribute to the development and optimization of therapeutic approaches against cancer, utilizing these phytoconstituents as ligands.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"89386322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-10DOI: 10.2174/1570180820666230710163705
C. A, J. Terán, H. Rodríguez-Matsui, David M. Aparicio-Solano, M. Orea
Chiral azepines are synthesized with remarkable diastereoselectivity, but their biological activity has not been investigated. However, benzazepines have demonstrated notable effects, particularly on the central nervous system (CNS) and infections. This characteristic attracts the interest of bioinformatic investigations in this new family, as their structural similarity can confirm their potential based on their kinship or discovering new options for biological potential. Possible interaction targets of previously synthesized chiral azepines are investigated. This study involves examining the interaction between these targets, conducting molecular docking analysis, ADME (administration, distribution, metabolism, excretion), and toxicology prediction to assess biological potential. Modeling 3D-optimized structural, virtual screening, molecular docking, ADME, and toxicological studies were performed. Structural analysis demonstrated potential against neurodegenerative diseases and cancer. In Molecular docking against cancer, pathways dependent on MAP2K1 and COX-2 exhibited energetically superior inhibitors than reference drugs, namely azepines 1, 3, and 6. Additionally, azepines 1 and 8 exhibited selective impacts against GSK3 and HMG-CoA-Reductase, respectively. Azepine 6 demonstrated an effect on CNS vs. GSK3 and HMG-CoA-Reductase, as well as potential against Alzheimer's disease; however, with a lower energy level with subunit 33 GABA-receptor. ADMETx investigations indicated satisfactory results for azepines. However, the opening of the cycle results in adverse effects and increased bioaccumulation, indicating the importance of preserving the integrity of azepine to propose its biological effect. Chiral azepines exhibit significant biological potential, particularly azepine 6 with a methyl substituent, which demonstrates multitarget potential. In addition, p-nitro phenyl substituent makes it highly selective towards CNS diseases. These findings indicate a strong relationship between biological activity and the stability of chiral azepines.
手性氮卓类化合物的合成具有明显的非对映选择性，但其生物活性尚未得到研究。然而，苯二氮卓类药物已显示出显著的效果，特别是对中枢神经系统(CNS)和感染。这一特征吸引了对这一新家族进行生物信息学研究的兴趣，因为它们的结构相似性可以根据它们的亲缘关系确认它们的潜力或发现新的生物潜力选择。研究了先前合成的手性氮卓类药物可能的相互作用靶点。本研究包括检测这些靶点之间的相互作用，进行分子对接分析，ADME(给药、分布、代谢、排泄)和毒理学预测，以评估生物潜力。建模3d优化结构，虚拟筛选，分子对接，ADME和毒理学研究进行。结构分析显示对神经退行性疾病和癌症有潜在的治疗作用。在对抗癌症的分子对接中，依赖于MAP2K1和COX-2的途径表现出比参比药物(即氮卓类药物1、3和6)更强的能量抑制剂。此外，azepines 1和8分别对GSK3和HMG-CoA-Reductase表现出选择性作用。Azepine 6对中枢神经系统与GSK3和hmg - coa -还原酶的作用，以及对阿尔茨海默病的潜在作用;然而，与亚基33 gaba受体的能量水平较低。ADMETx调查显示，氮卓类药物的效果令人满意。然而，循环的开启会导致不良反应和生物积累的增加，这表明保持氮卓的完整性对于提出其生物效应的重要性。手性氮卓类化合物具有重要的生物学潜力，特别是甲基取代的氮卓6具有多靶点潜力。此外，对硝基苯基取代基使其对中枢神经系统疾病具有高度选择性。这些发现表明，生物活性与手性氮卓类药物的稳定性之间存在很强的关系。
{"title":"Chiral azepines: In silico potential in cancer and neurodegenerative diseases, a chemical analysis","authors":"C. A, J. Terán, H. Rodríguez-Matsui, David M. Aparicio-Solano, M. Orea","doi":"10.2174/1570180820666230710163705","DOIUrl":"https://doi.org/10.2174/1570180820666230710163705","url":null,"abstract":"\u0000\u0000Chiral azepines are synthesized with remarkable diastereoselectivity, but their biological activity has not been investigated. However, benzazepines have demonstrated notable effects, particularly on the central nervous system (CNS) and infections. This characteristic attracts the interest of bioinformatic investigations in this new family, as their structural similarity can confirm their potential based on their kinship or discovering new options for biological potential.\u0000\u0000\u0000\u0000Possible interaction targets of previously synthesized chiral azepines are investigated. This study involves examining the interaction between these targets, conducting molecular docking analysis, ADME (administration, distribution, metabolism, excretion), and toxicology prediction to assess biological potential.\u0000\u0000\u0000\u0000Modeling 3D-optimized structural, virtual screening, molecular docking, ADME, and toxicological studies were performed.\u0000\u0000\u0000\u0000Structural analysis demonstrated potential against neurodegenerative diseases and cancer. In Molecular docking against cancer, pathways dependent on MAP2K1 and COX-2 exhibited energetically superior inhibitors than reference drugs, namely azepines 1, 3, and 6. Additionally, azepines 1 and 8 exhibited selective impacts against GSK3 and HMG-CoA-Reductase, respectively. Azepine 6 demonstrated an effect on CNS vs. GSK3 and HMG-CoA-Reductase, as well as potential against Alzheimer's disease; however, with a lower energy level with subunit 33 GABA-receptor. ADMETx investigations indicated satisfactory results for azepines. However, the opening of the cycle results in adverse effects and increased bioaccumulation, indicating the importance of preserving the integrity of azepine to propose its biological effect.\u0000\u0000\u0000\u0000Chiral azepines exhibit significant biological potential, particularly azepine 6 with a methyl substituent, which demonstrates multitarget potential. In addition, p-nitro phenyl substituent makes it highly selective towards CNS diseases. These findings indicate a strong relationship between biological activity and the stability of chiral azepines.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75882406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-07-01DOI: 10.2174/1570180820666230701000317
Rajnish Kumar, Greesh Kumar, A. Mazumder, Salahuddin, Upendra Kumar
1,3,4-Oxadiazole is a five-membered heterocyclic compound with one oxygen, two nitrogen, and two carbon atoms arranged in a ring. Several research reports, patents, and marketed drugs have already established 1,3,4-oxadiazole and its analog as potential molecules having a diverse range of pharmacological activities. In this review, we focused on recently acknowledged straightforward synthesis approaches for 1,3,4-oxadiazole and its analogs. Additionally, interactions of the 1,3,4-oxadiazole derivative with different biological targets (enzymes and receptors) have been described. The present findings discussed in this review analysis will aid researchers in conducting future research on 1,3,4-oxadiazole.
{"title":"1,3,4-Oxadiazole and its Analogs: Recently Adopted Synthetic Approaches and Interaction with Targets","authors":"Rajnish Kumar, Greesh Kumar, A. Mazumder, Salahuddin, Upendra Kumar","doi":"10.2174/1570180820666230701000317","DOIUrl":"https://doi.org/10.2174/1570180820666230701000317","url":null,"abstract":"\u0000\u00001,3,4-Oxadiazole is a five-membered heterocyclic compound with one oxygen, two nitrogen, and two carbon atoms arranged in a ring. Several research reports, patents, and marketed drugs have already established 1,3,4-oxadiazole and its analog as potential molecules having a diverse range of pharmacological activities. In this review, we focused on recently acknowledged straightforward synthesis approaches for 1,3,4-oxadiazole and its analogs. Additionally, interactions of the 1,3,4-oxadiazole derivative with different biological targets (enzymes and receptors) have been described. The present findings discussed in this review analysis will aid researchers in conducting future research on 1,3,4-oxadiazole.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78834439","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-26DOI: 10.2174/1570180820666230626161928
M. Bnouham, Khaoula Jamai, N. Daoudi, Amal Elrherabi
Pancreatic lipase is an enzyme that catalyzes the hydrolysis of triglycerides to monoglycerides and free fatty acids which promote and accelerate their absorption by the intestine, thus leading to obesity. Drugs that have numerous side effects explain the beneficial medicinal effect of plants resulting from their Phyto molecules that exhibit strong anti-lipase activity. The present review reveals the medical treatment and consequently the associated side effects. It also represents an update of various medicinal plants and their metabolites that act as lipase inhibitors published between (2020-2022). We have discussed 93 species belonging to 48 different plant families and numerous bioactive molecules exerting this activity. We have compared 29 species for their anti-lipase potential. Fabaceae and Lamiaceae were the most dominant with 7 species, and the highest percentage (95%) for pancreatic lipase inhibitory activity was recorded by “Filipendula kmtaschatia” from Rosaceae family while “Piper betle” from Piperaceae family showed the lowest percentage (15.9%). The medical treatments with low dose effect were liraglutide saxenda (3mg/day), also flavonoids, in particular catechin derivatives, which were the most potent in terms of pancreatic lipase inhibitory activity with the lowest IC50s. This study summarized medical and natural treatments that are used to treat obesity through inhibiting pancreatic lipase and delaying fat assimilation in the intestines. So far, more studies are needed for the use of these as herbal medicine for obesity.
{"title":"Medicinal plants and natural products to treat obesity through inhibiting pancreatic lipase: A review (2020-2022)","authors":"M. Bnouham, Khaoula Jamai, N. Daoudi, Amal Elrherabi","doi":"10.2174/1570180820666230626161928","DOIUrl":"https://doi.org/10.2174/1570180820666230626161928","url":null,"abstract":"\u0000\u0000Pancreatic lipase is an enzyme that catalyzes the hydrolysis of triglycerides to monoglycerides and free fatty acids which promote and accelerate their absorption by the intestine, thus leading to obesity. Drugs that have numerous side effects explain the beneficial medicinal effect of plants resulting from their Phyto molecules that exhibit strong anti-lipase activity.\u0000\u0000\u0000\u0000The present review reveals the medical treatment and consequently the associated side effects. It also represents an update of various medicinal plants and their metabolites that act as lipase inhibitors published between (2020-2022). We have discussed 93 species belonging to 48 different plant families and numerous bioactive molecules exerting this activity.\u0000\u0000\u0000\u0000We have compared 29 species for their anti-lipase potential. Fabaceae and Lamiaceae were the most dominant with 7 species, and the highest percentage (95%) for pancreatic lipase inhibitory activity was recorded by “Filipendula kmtaschatia” from Rosaceae family while “Piper betle” from Piperaceae family showed the lowest percentage (15.9%). The medical treatments with low dose effect were liraglutide saxenda (3mg/day), also flavonoids, in particular catechin derivatives, which were the most potent in terms of pancreatic lipase inhibitory activity with the lowest IC50s.\u0000\u0000\u0000\u0000This study summarized medical and natural treatments that are used to treat obesity through inhibiting pancreatic lipase and delaying fat assimilation in the intestines. So far, more studies are needed for the use of these as herbal medicine for obesity.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80223618","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}
Drug delivery to the brain is a challenging task as many drugs do not cross the blood-brain barrier (BBB). As a result, designing strategies to target drugs to the brain requires significant effort. However, recent research has focused on the administration of drugs through the nose to the brain, a non-invasive way to bypass the BBB and deliver therapeutic molecules directly to the brain. Nose-to-brain drug delivery is a promising approach that allows for the direct transportation of therapeutic molecules to the brain while increasing drug concentration in the brain. This approach has gained considerable attention due to its non-invasive nature, which makes it feasible, reliable, and efficient. One promising approach for nose-to-brain drug delivery is the use of nanoparticles as a platform for drug and gene delivery. Nanoparticles offer several advantages, including the ability to protect therapeutic drugs from degradation and increase the efficacy of drug delivery due to their unique size, shape, and surface features. Nanoparticles can also be engineered to target specific cells or tissues, enabling more precise drug delivery to the brain. The use of nanoparticles for nose-to-brain drug delivery has been extensively studied, and recent developments have shown promising results. In addition, patents relating to medication targeting via the nasal route have been developed. These patents cover various aspects of drug delivery, including the use of different types of nanoparticles, methods for producing nanoparticles, and methods for delivering nanoparticles to the brain.
{"title":"Nanotechnology-Based Approaches for Nose-to-Brain Drug Delivery in Neurodegenerative Diseases","authors":"Sudhanshu Mishra, Saurabh Kumar Gupta, Sugat Shukla, Srishti Tiwari, Ragghee Bhattacharya, Smriti Ojha","doi":"10.2174/1570180820666230622120759","DOIUrl":"https://doi.org/10.2174/1570180820666230622120759","url":null,"abstract":"\u0000\u0000Drug delivery to the brain is a challenging task as many drugs do not cross the blood-brain barrier (BBB). As a result, designing strategies to target drugs to the brain requires significant effort. However, recent research has focused on the administration of drugs through the nose to the brain, a non-invasive way to bypass the BBB and deliver therapeutic molecules directly to the brain. Nose-to-brain drug delivery is a promising approach that allows for the direct transportation of therapeutic molecules to the brain while increasing drug concentration in the brain. This approach has gained considerable attention due to its non-invasive nature, which makes it feasible, reliable, and efficient. One promising approach for nose-to-brain drug delivery is the use of nanoparticles as a platform for drug and gene delivery. Nanoparticles offer several advantages, including the ability to protect therapeutic drugs from degradation and increase the efficacy of drug delivery due to their unique size, shape, and surface features. Nanoparticles can also be engineered to target specific cells or tissues, enabling more precise drug delivery to the brain. The use of nanoparticles for nose-to-brain drug delivery has been extensively studied, and recent developments have shown promising results. In addition, patents relating to medication targeting via the nasal route have been developed. These patents cover various aspects of drug delivery, including the use of different types of nanoparticles, methods for producing nanoparticles, and methods for delivering nanoparticles to the brain.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86614584","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-19DOI: 10.2174/1570180820666230619094409
Z. Fatima, S. Nandi, Muneer Alam
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). It is one of the leading causes of death of 1.5 million people each year. TB can be treated by directly observed treatment short course (DOTS), but due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, consequences can be devastating if the single DOTS dose is missed by the patient. MDR and XDR-TB require much more attention and time to control the infection. The longer period of tuberculosis treatment has side effects and it is expensive. This alarming condition demands the development of novel processes to diagnose the disease in its early stage as well as to produce more promising antimicrobial chemotherapeutics. The current study aimed to explore molecular mechanisms involving docking simulation-based quantitative structure-amino acid relationship (QSAAR) in order to have a better understanding of the interactions between the fluoroquinolones and Mtb DNA gyrase. In this study, 24 fluoroquinolone (FQ) compounds present in the literature were selected and docked against the Mtb DNA gyrase. Further, the relationship between the minimum inhibitory concentration of the compounds and interacting amino acids was assessed using QSAAR. Results The study has established a novel method of formulating a quantitative structure-amino acid relationship. A significant correlation (R-value=0.829) between biological activity and the docked amino acid residues responsible for producing anti-tubercular activities has been obtained The predicted residues captured in the developed model have been explored to report the Mtb virulence.
{"title":"Exploring the Biochemical Mechanisms of Fluoroquinolone Compounds against Tuberculosis by Utilizing Molecular Docking and Quantitative Structure-Amino Acid Relationship","authors":"Z. Fatima, S. Nandi, Muneer Alam","doi":"10.2174/1570180820666230619094409","DOIUrl":"https://doi.org/10.2174/1570180820666230619094409","url":null,"abstract":"\u0000\u0000Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis (Mtb). It is one of the leading causes of death of 1.5 million people each year. TB can be treated by directly observed treatment short course (DOTS), but due to multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis, consequences can be devastating if the single DOTS dose is missed by the patient. MDR and XDR-TB require much more attention and time to control the infection. The longer period of tuberculosis treatment has side effects and it is expensive.\u0000\u0000\u0000\u0000This alarming condition demands the development of novel processes to diagnose the disease in its early stage as well as to produce more promising antimicrobial chemotherapeutics. The current study aimed to explore molecular mechanisms involving docking simulation-based quantitative structure-amino acid relationship (QSAAR) in order to have a better understanding of the interactions between the fluoroquinolones and Mtb DNA gyrase.\u0000\u0000\u0000\u0000In this study, 24 fluoroquinolone (FQ) compounds present in the literature were selected and docked against the Mtb DNA gyrase. Further, the relationship between the minimum inhibitory concentration of the compounds and interacting amino acids was assessed using QSAAR. Results\u0000\u0000\u0000\u0000The study has established a novel method of formulating a quantitative structure-amino acid relationship. A significant correlation (R-value=0.829) between biological activity and the docked amino acid residues responsible for producing anti-tubercular activities has been obtained\u0000\u0000\u0000\u0000The predicted residues captured in the developed model have been explored to report the Mtb virulence.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75086939","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-14DOI: 10.2174/1570180820666230614121851
Rakhi Mishra, Varsha Jindaniya, A. Mazumder, Shivani Tyagi
Thiosemicarbazide is an important substance in the synthesis of pharmacological and bioactive substances, and it is commonly used in the discovery of new medications. Multiple synthetic approaches exist for the creation of different thiosemicarbazide analogs, which are then discovered to treat a variety of diseases. This review paper aims to determine the growing importance of thiosemicarbazide analogs in various types of sickness by examining various unique synthetic methods that have been described to manufacture them. To incorporate published research and review papers, a comprehensive review of the literature from many sources during the past 24 years was conducted. This paper summarises the findings of a literature review about the synthesis and biological activity of thiosemicarbazide and thiosemicarbazone derivatives. Numerous new studies on the role of thiosemicarbazide and thiosemicarbazone derivatives, as well as their methods of production and biological activity for various forms of the disease, are discussed in this review article.
{"title":"Synthesis and Diverse Pharmacological actions of Thiosemicarbazide Analogs: A Review","authors":"Rakhi Mishra, Varsha Jindaniya, A. Mazumder, Shivani Tyagi","doi":"10.2174/1570180820666230614121851","DOIUrl":"https://doi.org/10.2174/1570180820666230614121851","url":null,"abstract":"\u0000\u0000Thiosemicarbazide is an important substance in the synthesis of pharmacological and bioactive substances, and it is commonly used in the discovery of new medications. Multiple synthetic approaches exist for the creation of different thiosemicarbazide analogs, which are then discovered to treat a variety of diseases.\u0000\u0000\u0000\u0000This review paper aims to determine the growing importance of thiosemicarbazide analogs in various types of sickness by examining various unique synthetic methods that have been described to manufacture them.\u0000\u0000\u0000\u0000To incorporate published research and review papers, a comprehensive review of the literature from many sources during the past 24 years was conducted.\u0000\u0000\u0000\u0000This paper summarises the findings of a literature review about the synthesis and biological activity of thiosemicarbazide and thiosemicarbazone derivatives.\u0000\u0000\u0000\u0000Numerous new studies on the role of thiosemicarbazide and thiosemicarbazone derivatives, as well as their methods of production and biological activity for various forms of the disease, are discussed in this review article.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78045152","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-13DOI: 10.2174/1570180820666230613152134
Rajiv Sharma, A. Gill, S. Gautam, Amanda Frank, Neha Bajwa, P. Singh
Colorectal cancer is more prevalent in females than males. There are many anticancer drugs accessible for use, but their therapeutic importance is constrained by factors including poor solubility, low absorption, and multi-drug resistance. This review highlights how PLGA may be used to develop polymeric-targeted drug delivery systems that specifically target colorectal cancer. The PLGA polymer, which is disseminated in the colon together with drugs in a regulated and targeted manner, has the distinct characteristics of smart degradation in a biological system. Its degradability is dependent on multiple glycolide units; therefore, a lower glycol concentration improves degradability and vice versa. Also, PLGA facilitates drug delivery in colorectal cancer, enhances the efficacy of the drug, improves the sustained release profile of a drug, improves bioavailability due to prolonged retention time in the colon, enhances solubility, etc. To develop the formulation for improving the cytotoxic impact of various anticancer drugs, the surface modification of PLGA can be carried out by introducing a copolymer. By emphasizing their crucial characterization to demonstrate their therapeutic potential, this literature work has also shed light on recent patents and advancements in PLGA application.
{"title":"Implementation of PLGA-based nanoparticles for treatment of Colorectal Cancer","authors":"Rajiv Sharma, A. Gill, S. Gautam, Amanda Frank, Neha Bajwa, P. Singh","doi":"10.2174/1570180820666230613152134","DOIUrl":"https://doi.org/10.2174/1570180820666230613152134","url":null,"abstract":"\u0000\u0000Colorectal cancer is more prevalent in females than males. There are many anticancer drugs accessible for use, but their therapeutic importance is constrained by factors including poor solubility, low absorption, and multi-drug resistance. This review highlights how PLGA may be used to develop polymeric-targeted drug delivery systems that specifically target colorectal cancer. The PLGA polymer, which is disseminated in the colon together with drugs in a regulated and targeted manner, has the distinct characteristics of smart degradation in a biological system. Its degradability is dependent on multiple glycolide units; therefore, a lower glycol concentration improves degradability and vice versa. Also, PLGA facilitates drug delivery in colorectal cancer, enhances the efficacy of the drug, improves the sustained release profile of a drug, improves bioavailability due to prolonged retention time in the colon, enhances solubility, etc. To develop the formulation for improving the cytotoxic impact of various anticancer drugs, the surface modification of PLGA can be carried out by introducing a copolymer. By emphasizing their crucial characterization to demonstrate their therapeutic potential, this literature work has also shed light on recent patents and advancements in PLGA application.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76539493","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2023-06-13DOI: 10.2174/1570180820666230613163447
T. Bucciarelli, Francesco Corradi, Benedetta Bucciarelli, F. Bianco
Several studies have shown that high plasma concentrations of asymmetric dimethylarginine (ADMA), a known endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS), correlate with the severity of coronary artery disease (CAD), with worsening of cardiac ischemia/reperfusion (I/R) injury and coronary atherosclerosis. It is believed that it may be an important risk factor for myocardial infarction. ADMA, when in high concentrations, can determine a significant decrease in the synthesis and bioavailability of NO (Nitric oxide) and therefore alter the mechanisms of regulation of coronary vasodilation and vasomotor function of epicardial coronary arteries. Higher serum ADMA concentration is associated with worsening of post-ischemic remodeling since coronary angiogenesis, vasculogenesis, and collateral coronary growth are seriously impaired. In addition, there are reasons to believe that elevated plasma ADMA levels are related to the development of diseases affecting coronary microcirculation, such as ischemic non-obstructive coronary artery disease (INOCA). Methods: With the aim of providing the pharmacologist engaged in the design and discovery of new ADMA-lowering drugs with a complete examination of the subject, in this review, we discuss the most important studies related to the correlations between serum ADMA levels and cardiovascular diseases mentioned above. In addition, we critically discuss the main aspects of enzymology, synthesis, and metabolism of ADMA as a prerequisite for understanding the molecular mechanisms through which high concentrations of ADMA could contribute to promoting cardiovascular diseases. ADMA represents a new target for pharmacological modulation of cardiovascular endothelial function and therefore, there is a possibility of using selective pharmacological ADMA lowering drugs in cardiovascular disease with endothelial dysfunction and high plasma ADMA levels.
{"title":"Asymmetric Dimethylarginine (ADMA) in Cardiovascular Disease, Cardiac Ischemia/reperfusion Injury, and Ischemic Non-obstructive Coronary Artery Disease: Biochemical and Pharmacological Implications","authors":"T. Bucciarelli, Francesco Corradi, Benedetta Bucciarelli, F. Bianco","doi":"10.2174/1570180820666230613163447","DOIUrl":"https://doi.org/10.2174/1570180820666230613163447","url":null,"abstract":"\u0000\u0000Several studies have shown that high plasma concentrations of asymmetric dimethylarginine (ADMA), a known endogenous competitive inhibitor of endothelial nitric oxide synthase (eNOS), correlate with the severity of coronary artery disease (CAD), with worsening of cardiac ischemia/reperfusion (I/R) injury and coronary atherosclerosis. It is believed that it may be an important risk factor for myocardial infarction. ADMA, when in high concentrations, can determine a significant decrease in the synthesis and bioavailability of NO (Nitric oxide) and therefore alter the mechanisms of regulation of coronary vasodilation and vasomotor function of epicardial coronary arteries. Higher serum ADMA concentration is associated with worsening of post-ischemic remodeling since coronary angiogenesis, vasculogenesis, and collateral coronary growth are seriously impaired. In addition, there are reasons to believe that elevated plasma ADMA levels are related to the development of diseases affecting coronary microcirculation, such as ischemic non-obstructive coronary artery disease (INOCA).\u0000\u0000\u0000\u0000Methods: With the aim of providing the pharmacologist engaged in the design and discovery of new ADMA-lowering drugs with a complete examination of the subject, in this review, we discuss the most important studies related to the correlations between serum ADMA levels and cardiovascular diseases mentioned above. In addition, we critically discuss the main aspects of enzymology, synthesis, and metabolism of ADMA as a prerequisite for understanding the molecular mechanisms through which high concentrations of ADMA could contribute to promoting cardiovascular diseases.\u0000\u0000\u0000\u0000ADMA represents a new target for pharmacological modulation of cardiovascular endothelial function and therefore, there is a possibility of using selective pharmacological ADMA lowering drugs in cardiovascular disease with endothelial dysfunction and high plasma ADMA levels.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-06-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83030523","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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