Letters in Drug Design & Discovery最新文献

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}

{"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}