Pub Date : 2024-07-10DOI: 10.2174/0115701808306429240703100350
Luca Mendes Lampert, Bruno Ruszczyk Machado, Angélica Rocha Joaquim, Fernando Fumagalli
Background: Lead-like drugs, which present molecular weight (MW) < 300 Da, occupy an important space in the pharmaceutical area. Most of these small molecules have ring systems, which are important for their physicochemical properties and biological activity. Previous studies have evaluated ring systems in historic drugs or drug candidates in clinical trials. Objective: The purpose of this work was to analyze ring systems, focusing on this group of drugs with MW < 300 Da, to obtain specific insights. Methods: The lead-like drugs (n = 219) were obtained from previous publications and the new FDA drug approvals were obtained after that and analyzed using the DataWarrior software. Results: Most of the lead-like drugs (> 92%) present one or two rings, with the benzene ring and heterocycle ring systems being predominant. Pyridine, imidazole, piperidine, 4,5-dihydro-1Himidazole, and indole are the most frequent heterocycles in this set. The higher frequency of the 4,5- dihydro-1H-imidazole ring in the lead-like drugs is worth noting, as it is not observed in other drugs. The introduction of new rings has been similar in the lead-like drugs and the historic drugs, over the years; an example would be the 1,2,4-thiadiazinane 1,1-dioxide, which is present in the antimicrobial Taurolidine, a lead-like drug, and engages in the metabolic activation of the drug. Conclusion: In general, the ring systems in the lead-like drugs appear to follow similar patterns to the historic drugs. Additionally, few new ring systems are being introduced, which suggests that this is an emergent field to be explored in drug discovery.
背景：分子量（MW）为 300 Da 的类铅药物在制药领域占有重要地位。这些小分子大多具有环系统，这对其理化性质和生物活性非常重要。以往的研究已经对历史药物或临床试验候选药物中的环系统进行了评估。目的：这项工作的目的是分析环系统，重点是分子量为 300 Da 的这类药物，以获得具体的见解。研究方法从以前的出版物中获得类先导药物（n = 219），之后获得 FDA 的新药批准，并使用 DataWarrior 软件进行分析。结果大多数类先导药物（> 92%）都有一个或两个环，其中以苯环和杂环系统为主。吡啶、咪唑、哌啶、4,5-二氢-1-咪唑和吲哚是最常见的杂环。值得注意的是，4,5-二氢-1H-咪唑环在类铅药物中出现的频率较高，这在其他药物中没有发现。多年来，类铅药物和历史药物中引入新环的情况类似；例如，抗菌药陶乐定（Taurolidine）中含有 1,2,4-噻二嗪环 1,1-二氧化物，它参与了药物的代谢活化。结论总的来说，类铅药物中的环系统似乎与历史药物的模式相似。此外，很少有新的环系统出现，这表明这是药物发现中有待探索的一个新兴领域。
{"title":"Rings in “Lead-like Drugs”","authors":"Luca Mendes Lampert, Bruno Ruszczyk Machado, Angélica Rocha Joaquim, Fernando Fumagalli","doi":"10.2174/0115701808306429240703100350","DOIUrl":"https://doi.org/10.2174/0115701808306429240703100350","url":null,"abstract":"Background: Lead-like drugs, which present molecular weight (MW) < 300 Da, occupy an important space in the pharmaceutical area. Most of these small molecules have ring systems, which are important for their physicochemical properties and biological activity. Previous studies have evaluated ring systems in historic drugs or drug candidates in clinical trials. Objective: The purpose of this work was to analyze ring systems, focusing on this group of drugs with MW < 300 Da, to obtain specific insights. Methods: The lead-like drugs (n = 219) were obtained from previous publications and the new FDA drug approvals were obtained after that and analyzed using the DataWarrior software. Results: Most of the lead-like drugs (> 92%) present one or two rings, with the benzene ring and heterocycle ring systems being predominant. Pyridine, imidazole, piperidine, 4,5-dihydro-1Himidazole, and indole are the most frequent heterocycles in this set. The higher frequency of the 4,5- dihydro-1H-imidazole ring in the lead-like drugs is worth noting, as it is not observed in other drugs. The introduction of new rings has been similar in the lead-like drugs and the historic drugs, over the years; an example would be the 1,2,4-thiadiazinane 1,1-dioxide, which is present in the antimicrobial Taurolidine, a lead-like drug, and engages in the metabolic activation of the drug. Conclusion: In general, the ring systems in the lead-like drugs appear to follow similar patterns to the historic drugs. Additionally, few new ring systems are being introduced, which suggests that this is an emergent field to be explored in drug discovery.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141585552","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}
: Herbal and dietary supplements are products that add more nutritional value to the diet. The use of these products has increased worldwide and has become widespread. Recently, the food products market has witnessed significant advancements in improving the health and well-being of individuals with increased nutritional requirements or in preventing related diseases and issues. Overall, dietary supplements possess pharmacological properties that are not crucial for disease control, such as high blood pressure but are essential for various physiological processes. To report the recent pre-clinically and clinically proven benefits of different hypertension treatments, an extensive literature search was conducted using widely available scientific databases of oral supplements. This review aims to raise awareness about commonly used dietary and herbal products, particularly among individuals with high blood pressure. Additionally, this paper highlights several nutritional supplements that hold promise for future research.
{"title":"Herbal and Dietary supplements for Hypertension Management.","authors":"Mounia Driouech, Mounime Kadi, Abderrahim Ziyyat, Hassane Mekhfi, Mohamed Bnouham, Abdelkhaleq Legssyer","doi":"10.2174/0115701808297606240628065101","DOIUrl":"https://doi.org/10.2174/0115701808297606240628065101","url":null,"abstract":": Herbal and dietary supplements are products that add more nutritional value to the diet. The use of these products has increased worldwide and has become widespread. Recently, the food products market has witnessed significant advancements in improving the health and well-being of individuals with increased nutritional requirements or in preventing related diseases and issues. Overall, dietary supplements possess pharmacological properties that are not crucial for disease control, such as high blood pressure but are essential for various physiological processes. To report the recent pre-clinically and clinically proven benefits of different hypertension treatments, an extensive literature search was conducted using widely available scientific databases of oral supplements. This review aims to raise awareness about commonly used dietary and herbal products, particularly among individuals with high blood pressure. Additionally, this paper highlights several nutritional supplements that hold promise for future research.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141585451","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-07-02DOI: 10.2174/0115701808303890240620074039
Karla Joane da Silva Menezes, Fernanda De França Genuíno Ramos Campos, Marianny de Souza, Daniel Calazans Medeiros, Igor José dos Santos Nascimento, Ricardo Olimpio de Moura
Background: Inflammation is an immunological reaction against an aggressor agent. NLRP3 inflammasome is a component of the immune system, which, when excessively activated, results in several inflammatory diseases, making it an attractive target for discovering antiinflammatory drugs. Computer-Aided Drug Design (CADD) techniques are powerful tools used to search for new drugs in less time and financial cost. Recently, studies demonstrated the CADD methods to discover information about NLRP3 inhibitors MCC950 and NP3-146. In addition, the discovery of GDC-2394 and its evaluation in clinical trials instigate new studies to find binding modes and structural attributes that can used in drug design works against this target. Objectives: Here, molecular modeling methods were used to discover the significant interactions of GDC-2394, MCC950, and NP3-146 with NLRP3 to obtain helpful information in drug design compared to other inhibitors. Methods: Molecular docking was performed using GOLD software. The best complexes were submitted into molecular dynamics simulations using GROMACS software, and the MM-PBSA was used to provide the free binding energy, which was performed using the tool g_mmpbsa compiled in GROMACS. Results: The RMSD, RMSF, Rg, SASA, and H-bond plots showed that the compound was stable during MD simulation time (100 ns) for GDC-2394. The PCA analysis for all compounds verified similar variance of the complex with the inhibitors to the apo-NLRP3, indicative of stability. DCCM analysis showed the best correlation in residues 134 - 371 region, which contains critical amino acids from the binding site (Ala227, Ala228, and Arg578), besides the newly identified residues. Using MMPBSA to provide the binding free energy, it was observed that the high affinity of the drugs against NLRP3 is related to the lower rigidity of the structure. Furthermore, we identified the critical residues Phe575, Pro352, Tyr632, and Met661 related to the coupling process. result: Then, RMSD, RMSF, Rg, SASA, and H-bond plots showed that the compound was stable during MD simulation time (100 ns) for GDC-2394. The PCA analysis for all compounds verified similar variance of the complex with the inhibitors to the apo-NLRP3, indicative of stability. Through DCCM analysis, the best correlation was observed in residues 134 - 371 region, which contains critical amino acids from the binding site (Ala227, Ala228, and Arg578), besides the newly identified residues. Using MM-PBSA to provide the binding free energy, it was observed that the high affinity of the drugs against NLRP3 is related to the lower rigidity of the structure. Furthermore, we identified the critical residues Phe575, Pro352, Tyr632, and Met661 related to the coupling process. Conclusion: Thus, these discoveries may contribute to the development of new anti-inflammatory drugs, such as NLRP3 inhibitors.
{"title":"Molecular Dynamics Simulations and Binding Free Energy Calculations to Discover New Insights into NLRP3 Inhibitors","authors":"Karla Joane da Silva Menezes, Fernanda De França Genuíno Ramos Campos, Marianny de Souza, Daniel Calazans Medeiros, Igor José dos Santos Nascimento, Ricardo Olimpio de Moura","doi":"10.2174/0115701808303890240620074039","DOIUrl":"https://doi.org/10.2174/0115701808303890240620074039","url":null,"abstract":"Background: Inflammation is an immunological reaction against an aggressor agent. NLRP3 inflammasome is a component of the immune system, which, when excessively activated, results in several inflammatory diseases, making it an attractive target for discovering antiinflammatory drugs. Computer-Aided Drug Design (CADD) techniques are powerful tools used to search for new drugs in less time and financial cost. Recently, studies demonstrated the CADD methods to discover information about NLRP3 inhibitors MCC950 and NP3-146. In addition, the discovery of GDC-2394 and its evaluation in clinical trials instigate new studies to find binding modes and structural attributes that can used in drug design works against this target. Objectives: Here, molecular modeling methods were used to discover the significant interactions of GDC-2394, MCC950, and NP3-146 with NLRP3 to obtain helpful information in drug design compared to other inhibitors. Methods: Molecular docking was performed using GOLD software. The best complexes were submitted into molecular dynamics simulations using GROMACS software, and the MM-PBSA was used to provide the free binding energy, which was performed using the tool g_mmpbsa compiled in GROMACS. Results: The RMSD, RMSF, Rg, SASA, and H-bond plots showed that the compound was stable during MD simulation time (100 ns) for GDC-2394. The PCA analysis for all compounds verified similar variance of the complex with the inhibitors to the apo-NLRP3, indicative of stability. DCCM analysis showed the best correlation in residues 134 - 371 region, which contains critical amino acids from the binding site (Ala227, Ala228, and Arg578), besides the newly identified residues. Using MMPBSA to provide the binding free energy, it was observed that the high affinity of the drugs against NLRP3 is related to the lower rigidity of the structure. Furthermore, we identified the critical residues Phe575, Pro352, Tyr632, and Met661 related to the coupling process. result: Then, RMSD, RMSF, Rg, SASA, and H-bond plots showed that the compound was stable during MD simulation time (100 ns) for GDC-2394. The PCA analysis for all compounds verified similar variance of the complex with the inhibitors to the apo-NLRP3, indicative of stability. Through DCCM analysis, the best correlation was observed in residues 134 - 371 region, which contains critical amino acids from the binding site (Ala227, Ala228, and Arg578), besides the newly identified residues. Using MM-PBSA to provide the binding free energy, it was observed that the high affinity of the drugs against NLRP3 is related to the lower rigidity of the structure. Furthermore, we identified the critical residues Phe575, Pro352, Tyr632, and Met661 related to the coupling process. Conclusion: Thus, these discoveries may contribute to the development of new anti-inflammatory drugs, such as NLRP3 inhibitors.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141530637","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 : 2024-06-26DOI: 10.2174/0115701808294306240613104855
Ibrahim Mhaidat, lena tahat, Ghada Alomari, Laiali AL-Quraan, Abeer Gharaibeh, Bahaa Al-Trad
Background: Oxidative stress plays a key role in the development of a wide range of diseases, including diabetes and cancer. Recent studies reported that the derivatives of triazole compounds have a potent antioxidant activity. Therefore, this study was designed to investigate the hepatoprotective effect of a novel newly synthesized 5-mercapto-1,2,4-triazole based on nalidixic acid [1-ethyl-3-(5-mercapto-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)-7-methyl-1,8-naphthyridin] (MTTN) 3 compound against CCl4 induced oxidative stress in mice. Materials and Methods: The MTTN compound was synthesized through the interaction and then cyclization of p-tolylisothiocyanate with nalidixic acid hydrazide. By using 1 H-NMR, 13C-NMR, IR, and elemental analyses, the structure of the newly synthesized MTTN compound was identified. To investigate the hepatoprotective effect of this compound, forty BALB/c mice were divided into four groups (n=10) as follows: the control group, the oxidative stress-induced group, which was intraperitoneally injected with 10% CCl4 (2 mL/kg), one pre-treatment group, which was treated orally with 200 mg/kg of MTTN compound for 8 days before being treated with CCl4 at day 8, and one post-treatment group, which was treated orally with 200 mg/kg of MTTN compound for 8 days simultaneously with CCl4 co-administration at days 3 and 5. At day 9, animals were scarified and serum and liver samples were collected. Results: CCl4 administration caused significant hepatotoxicity as evidenced by marked elevation in the serum activity of the liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and high blood cholesterol levels. Furthermore, the hepatic malondialdehyde (MDA) level, a marker of lipid peroxidation, was increased with CCl4 administration that was associated with a decrease in the hepatic superoxide dismutase (SOD) and catalase (CAT) activities (p < 0.05). However, pre and post-treatment with the new newly synthesized MTTN compound significantly reduced the serum levels of AST, ALT, and cholesterol and reduced hepatic oxidative stress as indicated by the decrease in the hepatic MDA level and the increases in the SOD and CAT activities (p < 0.05). Conclusion: This study suggests that the newly synthesized MTTN compound has a potent antioxidant property and can protect against CCl4-induced liver injury. Thus, with more clinical studies, this compound may be used as effective therapeutic agents against oxidative stress related diseases.
{"title":"The Hepatoprotective Effect of a Newly Synthesized 5-Mercapto-1,2,4-Triazole Derivative based on Nalidixic Acid Against Ccl4 induced Oxidative Stress in Mice","authors":"Ibrahim Mhaidat, lena tahat, Ghada Alomari, Laiali AL-Quraan, Abeer Gharaibeh, Bahaa Al-Trad","doi":"10.2174/0115701808294306240613104855","DOIUrl":"https://doi.org/10.2174/0115701808294306240613104855","url":null,"abstract":"Background: Oxidative stress plays a key role in the development of a wide range of diseases, including diabetes and cancer. Recent studies reported that the derivatives of triazole compounds have a potent antioxidant activity. Therefore, this study was designed to investigate the hepatoprotective effect of a novel newly synthesized 5-mercapto-1,2,4-triazole based on nalidixic acid [1-ethyl-3-(5-mercapto-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)-7-methyl-1,8-naphthyridin] (MTTN) 3 compound against CCl4 induced oxidative stress in mice. Materials and Methods: The MTTN compound was synthesized through the interaction and then cyclization of p-tolylisothiocyanate with nalidixic acid hydrazide. By using 1 H-NMR, 13C-NMR, IR, and elemental analyses, the structure of the newly synthesized MTTN compound was identified. To investigate the hepatoprotective effect of this compound, forty BALB/c mice were divided into four groups (n=10) as follows: the control group, the oxidative stress-induced group, which was intraperitoneally injected with 10% CCl4 (2 mL/kg), one pre-treatment group, which was treated orally with 200 mg/kg of MTTN compound for 8 days before being treated with CCl4 at day 8, and one post-treatment group, which was treated orally with 200 mg/kg of MTTN compound for 8 days simultaneously with CCl4 co-administration at days 3 and 5. At day 9, animals were scarified and serum and liver samples were collected. Results: CCl4 administration caused significant hepatotoxicity as evidenced by marked elevation in the serum activity of the liver enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and high blood cholesterol levels. Furthermore, the hepatic malondialdehyde (MDA) level, a marker of lipid peroxidation, was increased with CCl4 administration that was associated with a decrease in the hepatic superoxide dismutase (SOD) and catalase (CAT) activities (p < 0.05). However, pre and post-treatment with the new newly synthesized MTTN compound significantly reduced the serum levels of AST, ALT, and cholesterol and reduced hepatic oxidative stress as indicated by the decrease in the hepatic MDA level and the increases in the SOD and CAT activities (p < 0.05). Conclusion: This study suggests that the newly synthesized MTTN compound has a potent antioxidant property and can protect against CCl4-induced liver injury. Thus, with more clinical studies, this compound may be used as effective therapeutic agents against oxidative stress related diseases.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-06-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141503740","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 : 2024-05-31DOI: 10.2174/0115701808308364240422131751
Jingyao Kong, Xue Zhang, Guangshan Xuan
aims: Synthesis and screening of some novel sulfonamide derivatives with antibacterial and enzyme inhibitory effects. background: Currently, microbial infections are a global threat to human health and there is an urgent need to develop new and effective antimicrobial drugs to treat microbial infections. Carbonic anhydrase II is associated with a variety of diseases in vivo, and the development of carbonic anhydrase II inhibitors has far-reaching implications for the treatment of a wide range of diseases. objective: Synthesis of some novel sulfonamide derivatives containing pyrazole, 1,2,3-triazole and investigation of antimicrobial and enzyme inhibitory activities of the synthesised compounds. method: The compounds with bacteriostatic effect were screened by using the ring of inhibition method and MTT chromogenic method, and the mechanism of bacteriostatic inhibition and description of bacteriostatic effect of the synthesized compounds were investigated with the aid of MOE molecular docking simulation and Gaussian molecular weighting calculations. The in vitro inhibitory effect of the synthesized compounds on COX-2 was studied by phenylmethyl acetate colour development method. result: The results of bacterial inhibition experiments revealed that compounds 11d and 11e had better inhibition effects on pathogenic bacteria, especially on Candida albicans, which was essentially the same as that of the positive control FLUCZ. The compounds 4f, 7b and 11c were found to have the best inhibitory effect by COX-2 in vitro inhibition experiments, especially 11c, which had a better inhibitory effect than the positive control acetazolamide. conclusion: A series of derivatives obtained by introducing pyrazole and 1,2,3-triazole rings into sulfonamides have good bacteriostatic and COX-2 inhibition effects, and have the potential to be developed as novel antimicrobial agents and enzyme inhibitors. other: None other
目的：合成和筛选一些具有抗菌和酶抑制作用的新型磺酰胺衍生物：合成和筛选一些具有抗菌和酶抑制作用的新型磺酰胺衍生物。 背景：目前，微生物感染是威胁人类健康的全球性问题，迫切需要开发新型有效的抗菌药物来治疗微生物感染。体内碳酸酐酶 II 与多种疾病相关，开发碳酸酐酶 II 抑制剂对治疗多种疾病具有深远的意义：合成一些含有吡唑、1,2,3-三唑的新型磺酰胺衍生物，并研究合成化合物的抗菌活性和酶抑制活性：采用抑菌环法和 MTT 显色法筛选出具有抑菌作用的化合物，并借助 MOE 分子对接模拟和高斯分子权重计算研究了合成化合物的抑菌机理和抑菌效果描述。采用醋酸苯甲酯显色法研究了合成化合物对 COX-2 的体外抑制作用：抑菌实验结果表明，化合物 11d 和 11e 对致病菌有较好的抑制作用，特别是对白色念珠菌的抑制作用与阳性对照 FLUCZ 基本相同。通过 COX-2 体外抑制实验发现，化合物 4f、7b 和 11c 的抑制效果最好，尤其是 11c，其抑制效果优于阳性对照乙酰唑胺：在磺胺类药物中引入吡唑环和 1，2，3-三唑环得到的一系列衍生物具有良好的抑菌和抑制 COX-2 作用，有望开发为新型抗菌剂和酶抑制剂：无其他
{"title":"Synthesis, Characterization, Antibacterial Evaluation, and Enzyme Inhibition Activity of a Novel Nitrogen-containing Heterocyclic Sulfonamide","authors":"Jingyao Kong, Xue Zhang, Guangshan Xuan","doi":"10.2174/0115701808308364240422131751","DOIUrl":"https://doi.org/10.2174/0115701808308364240422131751","url":null,"abstract":"aims: Synthesis and screening of some novel sulfonamide derivatives with antibacterial and enzyme inhibitory effects. background: Currently, microbial infections are a global threat to human health and there is an urgent need to develop new and effective antimicrobial drugs to treat microbial infections. Carbonic anhydrase II is associated with a variety of diseases in vivo, and the development of carbonic anhydrase II inhibitors has far-reaching implications for the treatment of a wide range of diseases. objective: Synthesis of some novel sulfonamide derivatives containing pyrazole, 1,2,3-triazole and investigation of antimicrobial and enzyme inhibitory activities of the synthesised compounds. method: The compounds with bacteriostatic effect were screened by using the ring of inhibition method and MTT chromogenic method, and the mechanism of bacteriostatic inhibition and description of bacteriostatic effect of the synthesized compounds were investigated with the aid of MOE molecular docking simulation and Gaussian molecular weighting calculations. The in vitro inhibitory effect of the synthesized compounds on COX-2 was studied by phenylmethyl acetate colour development method. result: The results of bacterial inhibition experiments revealed that compounds 11d and 11e had better inhibition effects on pathogenic bacteria, especially on Candida albicans, which was essentially the same as that of the positive control FLUCZ. The compounds 4f, 7b and 11c were found to have the best inhibitory effect by COX-2 in vitro inhibition experiments, especially 11c, which had a better inhibitory effect than the positive control acetazolamide. conclusion: A series of derivatives obtained by introducing pyrazole and 1,2,3-triazole rings into sulfonamides have good bacteriostatic and COX-2 inhibition effects, and have the potential to be developed as novel antimicrobial agents and enzyme inhibitors. other: None other","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141192197","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 : 2024-04-30DOI: 10.2174/0115701808281133240424055511
Samuel Attah Egu, Sunday Okpanachi Idih, Favour Idih, Ruth Foluke Aminu, Lawrence Achimugu, Aminu Omale, Jamila Audu Omale, Lian Ojotule Abah, Emmanuel Amlabu
Background: Drug resistance poses a threat to global health given the disturbing rate at which microbiological illnesses are rising and the widespread use of antibiotics. While naturally occurring antibiotics reduce the likelihood of bacterial resistance, recognized drugs can develop the same properties when structurally modified. Metronidazole has been targeted to achieve this feat. Objective: The purpose of this work is to enable the structural modification of metronidazole by means of electric current, using inexpensive, easily accessible magnesium ribbon as electrodes in order to produce a novel, effective antibiotic. Method: With magnesium ribbon electrodes, metronidazole is modified electrochemically, in an undivided cell system. Ultraviolet-visible (UV-Vis), Fourier Transform Infrared (FTIR), and Gas Chromatography-Mass Spectrometry (GC-MS) were used to characterize the product. Antibacterial activity was evaluated using the agar well diffusion method and Wistar rats were used for in vivo toxicity assessment. Result: 2-Methyl-1-vinyl-1H-imidazol-5-amine showed good antibacterial activities compared to the standard nitrofurantoin and toxicity evaluations using Wistar rats revealed that the product might induce dose-dependent variations in kidney function biomarkers, with doses of 100 mg/kg and below. However, when the compound was administered orally, there was no significant effect on liver function, even at a dose of 1000 mg/kg. Conclusion: These results point to the modified metronidazole's potential as a potent antibiotic with controllable toxicity, indicating that additional research into its pharmacological uses is necessary.
{"title":"Electrochemical Modification of Metronidazole and its Application as Antibacterial and Potential Drug Agent","authors":"Samuel Attah Egu, Sunday Okpanachi Idih, Favour Idih, Ruth Foluke Aminu, Lawrence Achimugu, Aminu Omale, Jamila Audu Omale, Lian Ojotule Abah, Emmanuel Amlabu","doi":"10.2174/0115701808281133240424055511","DOIUrl":"https://doi.org/10.2174/0115701808281133240424055511","url":null,"abstract":"Background: Drug resistance poses a threat to global health given the disturbing rate at which microbiological illnesses are rising and the widespread use of antibiotics. While naturally occurring antibiotics reduce the likelihood of bacterial resistance, recognized drugs can develop the same properties when structurally modified. Metronidazole has been targeted to achieve this feat. Objective: The purpose of this work is to enable the structural modification of metronidazole by means of electric current, using inexpensive, easily accessible magnesium ribbon as electrodes in order to produce a novel, effective antibiotic. Method: With magnesium ribbon electrodes, metronidazole is modified electrochemically, in an undivided cell system. Ultraviolet-visible (UV-Vis), Fourier Transform Infrared (FTIR), and Gas Chromatography-Mass Spectrometry (GC-MS) were used to characterize the product. Antibacterial activity was evaluated using the agar well diffusion method and Wistar rats were used for in vivo toxicity assessment. Result: 2-Methyl-1-vinyl-1H-imidazol-5-amine showed good antibacterial activities compared to the standard nitrofurantoin and toxicity evaluations using Wistar rats revealed that the product might induce dose-dependent variations in kidney function biomarkers, with doses of 100 mg/kg and below. However, when the compound was administered orally, there was no significant effect on liver function, even at a dose of 1000 mg/kg. Conclusion: These results point to the modified metronidazole's potential as a potent antibiotic with controllable toxicity, indicating that additional research into its pharmacological uses is necessary.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140840003","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 : 2024-04-30DOI: 10.2174/0115701808296878240419065845
Sepehr Afsharipour, Mohammad Amin Raeisi Estabragh, Amirhossein Namaki, Mandana Ohadi, Mohammad Hassan Moshafi, Ibrahim M. Banat, Gholamreza Dehghannoudeh
Background: Temperature-sensitive (thermo-sensitive) formulations are a novel drug delivery dosage form that shows bio-inspired behavior in various applications. The structure and properties of a thermosensitive polymer are critical in designing an intelligent biometric polymer that contains lipopeptide biosurfactants. Objectives: In this study, thermo-sensitive hydrogels with lipopeptide biosurfactants as a potential wound dressing dosage form were formulated and examined regarding physicochemical properties. Methods: The lipopeptide biosurfactants were isolated from the Acinetobacter junni B6 bacterial strain and loaded on a formulation of poloxamer 407® and carboxymethyl cellulose as a gelling agent. Numerous experiments were carried out to evaluate the physicochemical properties of these formulations, such as the stability, spreadability, release profile, and kinetic. Results: The formulation (Poloxamer 407® (19% w/v), carboxymethyl cellulose (2% w/v), lipopeptide biosurfactants (5mg/mL), benzyl alcohol (1% v/v), and 0.1mL polyethylene glycol 400) was select as the optimum formulation. The selected formulation released 26.9% of the lipopeptide biosurfactants with anomalous transport kinetics after 10 hours. Conclusions: The results showed that a thermo-sensitive formulation could help achieve a sustained release of lipopeptide biosurfactants and potentially be used as a dressing formulation for wounds in future studies.
{"title":"Preparation and Physicochemical Properties of a Thermosensitive Hydrogel-based Lipopeptide Biosurfactant","authors":"Sepehr Afsharipour, Mohammad Amin Raeisi Estabragh, Amirhossein Namaki, Mandana Ohadi, Mohammad Hassan Moshafi, Ibrahim M. Banat, Gholamreza Dehghannoudeh","doi":"10.2174/0115701808296878240419065845","DOIUrl":"https://doi.org/10.2174/0115701808296878240419065845","url":null,"abstract":"Background: Temperature-sensitive (thermo-sensitive) formulations are a novel drug delivery dosage form that shows bio-inspired behavior in various applications. The structure and properties of a thermosensitive polymer are critical in designing an intelligent biometric polymer that contains lipopeptide biosurfactants. Objectives: In this study, thermo-sensitive hydrogels with lipopeptide biosurfactants as a potential wound dressing dosage form were formulated and examined regarding physicochemical properties. Methods: The lipopeptide biosurfactants were isolated from the Acinetobacter junni B6 bacterial strain and loaded on a formulation of poloxamer 407® and carboxymethyl cellulose as a gelling agent. Numerous experiments were carried out to evaluate the physicochemical properties of these formulations, such as the stability, spreadability, release profile, and kinetic. Results: The formulation (Poloxamer 407® (19% w/v), carboxymethyl cellulose (2% w/v), lipopeptide biosurfactants (5mg/mL), benzyl alcohol (1% v/v), and 0.1mL polyethylene glycol 400) was select as the optimum formulation. The selected formulation released 26.9% of the lipopeptide biosurfactants with anomalous transport kinetics after 10 hours. Conclusions: The results showed that a thermo-sensitive formulation could help achieve a sustained release of lipopeptide biosurfactants and potentially be used as a dressing formulation for wounds in future studies.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140839776","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 : 2024-04-19DOI: 10.2174/0115701808301580240405071948
Vijayalakshmi Gangadhara, Kavishankar Gawli, Asha Abraham
Background:: Investigating the structural attributes of the murine beta3-adrenergic receptor (β3-AR) is imperative for comprehending metabolic regulation, given its close resemblance to the human β3-AR. This receptor holds promise as a target for novel drug development against obesity and diabetes. Despite its potential, the absence of knowledge regarding the structure of murine β3- AR hampers a comprehensive understanding of its functionality. Objective:: Our study aimed to model the three-dimensional (3D) structure of murine β3-AR through various molecular structure prediction and simulation techniques, thus addressing the existing gap in structural information. Methods:: Employing diverse structure prediction programs, we refined the predicted structure of murine β3-AR. Primary sequence analysis offered insights into charge distribution, stability, and hydrophobic properties. The binding sites were identified in the modeled structure. Molecular Dynamics (MD) simulation provided the structural stability and dynamic behavior of the predicted β3- AR structure. Results:: The β3-AR protein exhibited specific characteristics, including a pI of 9.57, an aliphatic index of 98.35, a GRAVY score of 0.289, and the presence of conserved motifs and disulfide linkages. Utilizing the programs such as Phyre2, Swissmodel, I-Tasser, and AlphaFold2, we generated a 3D model of murine β3-AR. Subsequent refinement using ModRefiner revealed a structure comprising 13 helices, 2 strands, and 21 turns. The Ramachandran plot indicated favorable regions for 93.2% of residues, with minimal deviations. A 50 ns MD simulation demonstrated the consistent stability and integrity of the β3-AR protein. The top three binding pockets were identified based on varying areas and volumes. Dynamic behavior within residues Ser 252 and Arg 253 was observed, indicating flexibility in conformation. This study marks the first-ever exploration, offering initial structural insights into murine β3-AR. Conclusion:: This study underscores the critical role of computational approaches in predicting the 3D structure of β3-AR. We derived a refined model by employing diverse prediction techniques, elucidating key features. The findings emphasize the significance of this methodology in comprehending the structural foundation of β3-AR, providing valuable insights for targeted medication development against conditions such as obesity and diabetes.
{"title":"Structural Insights into Mouse β3-Adrenergic Receptor: A Promising Target for Obesity and Diabetes Therapeutics","authors":"Vijayalakshmi Gangadhara, Kavishankar Gawli, Asha Abraham","doi":"10.2174/0115701808301580240405071948","DOIUrl":"https://doi.org/10.2174/0115701808301580240405071948","url":null,"abstract":"Background:: Investigating the structural attributes of the murine beta3-adrenergic receptor (β3-AR) is imperative for comprehending metabolic regulation, given its close resemblance to the human β3-AR. This receptor holds promise as a target for novel drug development against obesity and diabetes. Despite its potential, the absence of knowledge regarding the structure of murine β3- AR hampers a comprehensive understanding of its functionality. Objective:: Our study aimed to model the three-dimensional (3D) structure of murine β3-AR through various molecular structure prediction and simulation techniques, thus addressing the existing gap in structural information. Methods:: Employing diverse structure prediction programs, we refined the predicted structure of murine β3-AR. Primary sequence analysis offered insights into charge distribution, stability, and hydrophobic properties. The binding sites were identified in the modeled structure. Molecular Dynamics (MD) simulation provided the structural stability and dynamic behavior of the predicted β3- AR structure. Results:: The β3-AR protein exhibited specific characteristics, including a pI of 9.57, an aliphatic index of 98.35, a GRAVY score of 0.289, and the presence of conserved motifs and disulfide linkages. Utilizing the programs such as Phyre2, Swissmodel, I-Tasser, and AlphaFold2, we generated a 3D model of murine β3-AR. Subsequent refinement using ModRefiner revealed a structure comprising 13 helices, 2 strands, and 21 turns. The Ramachandran plot indicated favorable regions for 93.2% of residues, with minimal deviations. A 50 ns MD simulation demonstrated the consistent stability and integrity of the β3-AR protein. The top three binding pockets were identified based on varying areas and volumes. Dynamic behavior within residues Ser 252 and Arg 253 was observed, indicating flexibility in conformation. This study marks the first-ever exploration, offering initial structural insights into murine β3-AR. Conclusion:: This study underscores the critical role of computational approaches in predicting the 3D structure of β3-AR. We derived a refined model by employing diverse prediction techniques, elucidating key features. The findings emphasize the significance of this methodology in comprehending the structural foundation of β3-AR, providing valuable insights for targeted medication development against conditions such as obesity and diabetes.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-04-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140628885","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 : 2024-04-17DOI: 10.2174/0115701808287616240321080922
Chunyi Lyu, Xuewei Yin, Zonghong Li, Teng Wang, Ruirong Xu
Background: Hedyotis diffusa Willd (HDW) is an herb that has been used empirically for treating cancer, and its antileukemic effect has been confirmed by laboratory evidence. This study aimed to explore the underlying mechanism by which HDW and its active compound exert effects on acute myeloid leukemia (AML) through in silico analyses combined with experimental validation. Methods: The targets of the compounds were collected from the database and intersected with AML targets. Based on these data, a protein-protein interaction (PPI) network and compound-target (C-T) network were constructed, and KEGG enrichment analysis was performed. Topological analysis of the C-T network and PPI network was performed to screen for hub compounds and targets. Molecular dynamics simulations were conducted to test the binding mode and strength between the targets and the compounds at the molecular level. Cell viability, flow cytometry, ELISA, and Q-PCR were further used to evaluate the in silico results. Results: A total of 86 targets of 12 screened active compounds of HDW against AML were identified. According to topological analysis, tumor protein p53 (TP53) and signal transducer and activator of transcription 3 (STAT3) exhibited the highest degree of centrality (DC) in the PPI networks of HDW targets. Quercetin had a higher affinity for TP53 than for STAT3. Molecular dynamics simulations confirmed that the TP53-quercetin docked complex was stable with respect to the original TP53-ligand complex. The targets of HDW and quercetin against AML were significantly enriched in multiple biological processes, including the p53 signaling pathway and apoptosis. The results from the in vitro experiment confirmed that quercetin triggers apoptosis in the human AML cell line KG-1 through the p53 pathway protein. Conclusion: This study outlines the multi-compound, multi-target, and multi-pathway mechanism by which HDW affects AML based on an in silico predictive model and further validates the antileukemic mechanism of the screened active compound in an in vitro model. This study provides a perspective for studying the antileukemic mechanism of HDW for further research.
背景：白花蛇舌草（Hedyotis diffusa Willd，HDW）是一种经验性用于治疗癌症的草药，其抗白血病作用已被实验室证据所证实。本研究旨在通过硅学分析结合实验验证，探索 HDW 及其活性化合物对急性髓性白血病（AML）产生影响的内在机制。研究方法从数据库中收集化合物的靶点并与急性髓性白血病靶点交叉。基于这些数据，构建了蛋白质-蛋白质相互作用（PPI）网络和化合物-靶点（C-T）网络，并进行了KEGG富集分析。对 C-T 网络和 PPI 网络进行拓扑分析，以筛选中心化合物和靶点。还进行了分子动力学模拟，以测试靶标与化合物在分子水平上的结合模式和强度。此外，还使用了细胞活力、流式细胞仪、ELISA 和 Q-PCR 等方法来评估硅学结果。结果筛选出的 12 种 HDW 活性化合物共鉴定出 86 个抗 AML 靶点。根据拓扑分析，肿瘤蛋白 p53（TP53）和信号转导和转录激活因子 3（STAT3）在 HDW 靶点的 PPI 网络中表现出最高的中心度（DC）。槲皮素对 TP53 的亲和力高于 STAT3。分子动力学模拟证实，TP53-槲皮素对接复合物与原始的TP53-配体复合物相比是稳定的。HDW和槲皮素针对急性髓细胞白血病的靶点在多个生物学过程中都有显著的富集，包括p53信号通路和细胞凋亡。体外实验结果证实，槲皮素可通过 p53 通路蛋白触发人 AML 细胞株 KG-1 的细胞凋亡。结论本研究基于硅学预测模型概述了 HDW 影响急性髓细胞性白血病的多化合物、多靶点和多途径机制，并在体外模型中进一步验证了所筛选的活性化合物的抗白血病机制。这项研究为进一步研究 HDW 的抗白血病机制提供了一个视角。
{"title":"Effects of Compound in Hedyotis diffusa Willd against Acute Myeloid Leukemia: An In silico and In vitro Study","authors":"Chunyi Lyu, Xuewei Yin, Zonghong Li, Teng Wang, Ruirong Xu","doi":"10.2174/0115701808287616240321080922","DOIUrl":"https://doi.org/10.2174/0115701808287616240321080922","url":null,"abstract":"Background: Hedyotis diffusa Willd (HDW) is an herb that has been used empirically for treating cancer, and its antileukemic effect has been confirmed by laboratory evidence. This study aimed to explore the underlying mechanism by which HDW and its active compound exert effects on acute myeloid leukemia (AML) through in silico analyses combined with experimental validation. Methods: The targets of the compounds were collected from the database and intersected with AML targets. Based on these data, a protein-protein interaction (PPI) network and compound-target (C-T) network were constructed, and KEGG enrichment analysis was performed. Topological analysis of the C-T network and PPI network was performed to screen for hub compounds and targets. Molecular dynamics simulations were conducted to test the binding mode and strength between the targets and the compounds at the molecular level. Cell viability, flow cytometry, ELISA, and Q-PCR were further used to evaluate the in silico results. Results: A total of 86 targets of 12 screened active compounds of HDW against AML were identified. According to topological analysis, tumor protein p53 (TP53) and signal transducer and activator of transcription 3 (STAT3) exhibited the highest degree of centrality (DC) in the PPI networks of HDW targets. Quercetin had a higher affinity for TP53 than for STAT3. Molecular dynamics simulations confirmed that the TP53-quercetin docked complex was stable with respect to the original TP53-ligand complex. The targets of HDW and quercetin against AML were significantly enriched in multiple biological processes, including the p53 signaling pathway and apoptosis. The results from the in vitro experiment confirmed that quercetin triggers apoptosis in the human AML cell line KG-1 through the p53 pathway protein. Conclusion: This study outlines the multi-compound, multi-target, and multi-pathway mechanism by which HDW affects AML based on an in silico predictive model and further validates the antileukemic mechanism of the screened active compound in an in vitro model. This study provides a perspective for studying the antileukemic mechanism of HDW for further research.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140615510","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 : 2024-04-17DOI: 10.2174/0115701808300981240408063655
Bin Zhou, Lisheng Wang, Yongquan Wei, Meiyan Jiang, Xingdong Wang
Background: Thirteen derivatives were designed and synthesized based on the excellent lead compound Matrine. Objective: This study aimed to discover novel anticancer agents with superior anticancer activity and to support the discovery of new drugs. Methods: The in vitro antiproliferative activity of all derivatives against four human cancer cells, A549, HGC-27, HCT-116, and HeLa, was determined by MTT. The best active compounds were subjected to cell cloning, migration, cell cycle and apoptosis, and molecular docking. Results: Compound 5XI showed the best activity against all four cell lines, especially against A549 cells, with an IC50 of 5.805 μmol/L. The antiproliferative activity of 5XI was much higher than that of matrine and only slightly weaker than that of Cisplatin, a multi-targeted small molecule inhibitor. 5XI also showed excellent inhibitory activity in cell cycle, apoptosis, cell scratch, and cell cloning assays and has shown good affinity in docking studies. Conclusion: 5XI has excellent antiproliferative activity, significantly inhibits cell cloning and migration, affects cancer cell cycle distribution, and induces apoptosis in a concentration-dependent manner, making it a potential anticancer drug agent.
{"title":"Design, Synthesis, and In vitro Biological Activities of Matrine Skeleton Derivatives as Potential Cancer Inhibitors","authors":"Bin Zhou, Lisheng Wang, Yongquan Wei, Meiyan Jiang, Xingdong Wang","doi":"10.2174/0115701808300981240408063655","DOIUrl":"https://doi.org/10.2174/0115701808300981240408063655","url":null,"abstract":"Background: Thirteen derivatives were designed and synthesized based on the excellent lead compound Matrine. Objective: This study aimed to discover novel anticancer agents with superior anticancer activity and to support the discovery of new drugs. Methods: The in vitro antiproliferative activity of all derivatives against four human cancer cells, A549, HGC-27, HCT-116, and HeLa, was determined by MTT. The best active compounds were subjected to cell cloning, migration, cell cycle and apoptosis, and molecular docking. Results: Compound 5XI showed the best activity against all four cell lines, especially against A549 cells, with an IC50 of 5.805 μmol/L. The antiproliferative activity of 5XI was much higher than that of matrine and only slightly weaker than that of Cisplatin, a multi-targeted small molecule inhibitor. 5XI also showed excellent inhibitory activity in cell cycle, apoptosis, cell scratch, and cell cloning assays and has shown good affinity in docking studies. Conclusion: 5XI has excellent antiproliferative activity, significantly inhibits cell cloning and migration, affects cancer cell cycle distribution, and induces apoptosis in a concentration-dependent manner, making it a potential anticancer drug agent.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":1.0,"publicationDate":"2024-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140617848","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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