The oral route is the most common route of administration of drugs. Over 90% of all the available marketed pharmaceutical products are oral formulations. Oral drugs are used in different courses of treatment including the prevention of tooth decay. Tooth decay is the permanent damage of the enamel which leads to the formation of cavities. It can be prevented with good oral hygiene and enough fluorides in the body. Fluorides can be administered both topically (toothpastes) and systemically (supplements). Fluoride supplements fall under oral drug delivery systems. They come in the form of tablets, lozenges, and liquids. However, challenges are faced when it comes to oral drug delivery in children. The development of paediatric drugs is a difficult undertaking since many pharmaceutically active compounds have low water solubility, instability, or an unpleasant taste. Children are unable to tolerate bitter or unpleasant-tasting formulations, as well as huge pills and capsules. Due to various biological, biochemical, and physical barriers faced by oral drug delivery systems, new approaches have been developed to address these challenges such as the application of nanotechnology in drug development. Jellies for oral administration on the other hand are a new approach for the delivery of drugs with bitter tastes as well as for age groups such as children and elders. They are clear, translucent, or non-greasy semisolid products that can be used both externally and internally. In-depth, aspects of these factors will be discussed in this review paper including oral dosage forms for paediatrics, tooth decay and its pathogenesis, preventive measures and setbacks of each measure as well as the future perspectives.
{"title":"Advanced Oral Drug Delivery Systems for Combating and Preventing Paediatric Periodontal Disease","authors":"Amanda Frank, P. Singh, Komal Singh, Saahil Arora, Rajiv Sharma, Neha Bajwa","doi":"10.2174/1570180820666230823093604","DOIUrl":"https://doi.org/10.2174/1570180820666230823093604","url":null,"abstract":"\u0000\u0000The oral route is the most common route of administration of drugs. Over 90% of all the available marketed pharmaceutical products are oral formulations. Oral drugs are used in different courses of treatment including the prevention of tooth decay.\u0000Tooth decay is the permanent damage of the enamel which leads to the formation of cavities. It can be prevented with good oral hygiene and enough fluorides in the body. Fluorides can be administered both topically (toothpastes) and systemically (supplements). Fluoride supplements fall under oral drug delivery systems. They come in the form of tablets, lozenges, and liquids. However, challenges are faced when it comes to oral drug delivery in children.\u0000The development of paediatric drugs is a difficult undertaking since many pharmaceutically active compounds have low water solubility, instability, or an unpleasant taste. Children are unable to tolerate bitter or unpleasant-tasting formulations, as well as huge pills and capsules. Due to various biological, biochemical, and physical barriers faced by oral drug delivery systems, new approaches have been developed to address these challenges such as the application of nanotechnology in drug development. Jellies for oral administration on the other hand are a new approach for the delivery of drugs with bitter tastes as well as for age groups such as children and elders. They are clear, translucent, or non-greasy semisolid products that can be used both externally and internally.\u0000In-depth, aspects of these factors will be discussed in this review paper including oral dosage forms for paediatrics, tooth decay and its pathogenesis, preventive measures and setbacks of each measure as well as the future perspectives.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91361484","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 : 2023-08-22DOI: 10.2174/1570180820666230822094954
Y. Najib, Y. Ayipo, Waleed A Alananzeh, Amar Ajmal, S. Shams, A. Wadood, M. Mordi
Parkinson’s disease (PD) is a chronic neurodegenerative disease affecting mostly aged people. The disease's symptoms develop gradually over time and include tremors, bradykinesia, rigidity, and postural instability. Current treatment options for PD are only symptom-targeted. Prolyl oligopeptidase (POP) is a serine protease enzymes implicated in PD pathogenesis via an increase in the aggregation of α-synuclein protein in the brain. This study aims to identify potent anti-PD ligands with inhibitory potential against POP Ligand-based pharmacophore modeling, Glide extra precision (XP) docking, and post-simulation analysis methods were used. The adopted ligand-based (LB) modeling generated pharmacophoric features, including 1 hydrophobic group, 1 positive ionizable group, 2 aromatic rings, and 2 hydrogen bond acceptors. A total of 23 hits with a Gunner-Henry score of 0.7 and an enrichment factor of 30.24 were obtained as validation protocols, making it an ideal model. The LB model retrieved 177 hit compounds from the 69,543 natural screening ligands available in the Interbioscreen database. Interestingly, ligands 1, 2, 3, 4, and 5 orderly demonstrated higher binding affinities with Glide XP docking of -9.0, -8.8, -8.7, -8.7, -8.7 kcal/mol compared to reference drugs, GSK552 and ZPP with -8.2, and -6.8 kcal/mol respectively. Similarly, their MM/GBSA values were recorded as -54.4, -51.3, -58.4, -49.3, - 33.5, & -32.5 kJ/mol respectively. Further, MD analysis indicated that ligands had higher favorable binding and stability to the receptor. Overall, the study paves the way for developing potential anti-PD therapeutics. The ligands are recommended as adjuvant/single candidate as anti-PD candidates upon further experiment.
帕金森病(PD)是一种以老年人为主的慢性神经退行性疾病。该病的症状随着时间的推移逐渐发展，包括震颤、运动迟缓、僵硬和姿势不稳定。目前PD的治疗方案仅针对症状。脯氨酸寡肽酶(POP)是一种丝氨酸蛋白酶，通过增加α-突触核蛋白在大脑中的聚集而参与PD的发病机制。本研究旨在通过基于popligand的药效体建模、Glide extra precision (XP)对接和模拟后分析方法，鉴定具有抑制潜力的有效抗pd配体。采用基于配体(LB)的模型生成了药效特征，包括1个疏水性基团、1个正离子基团、2个芳香环和2个氢键受体。共获得23个命中，Gunner-Henry得分为0.7，富集系数为30.24，是一个理想的模型。LB模型从Interbioscreen数据库中提供的69,543种天然筛选配体中检索了177种命中化合物。有趣的是，与对照药物GSK552和ZPP相比，配体1、2、3、4和5依次显示出更高的结合亲和力，其与Glide XP的对接度分别为-9.0、-8.8、-8.7、-8.7 kcal/mol，分别为-8.2和-6.8 kcal/mol。同样，它们的MM/GBSA值分别为-54.4、-51.3、-58.4、-49.3、- 33.5和-32.5 kJ/mol。此外，MD分析表明配体对受体具有更有利的结合和稳定性。总的来说，这项研究为开发潜在的抗pd疗法铺平了道路。在进一步的实验中，这些配体被推荐为抗pd的佐剂/单一候选体。
{"title":"Potent Small Molecules Inhibitors Discovery Through Ligand-based Modelling For Effective Treatment Of Parkinson’s Disease","authors":"Y. Najib, Y. Ayipo, Waleed A Alananzeh, Amar Ajmal, S. Shams, A. Wadood, M. Mordi","doi":"10.2174/1570180820666230822094954","DOIUrl":"https://doi.org/10.2174/1570180820666230822094954","url":null,"abstract":"\u0000\u0000Parkinson’s disease (PD) is a chronic neurodegenerative disease affecting mostly aged people. The disease's symptoms develop gradually over time and include tremors, bradykinesia, rigidity, and postural instability. Current treatment options for PD are only symptom-targeted. Prolyl oligopeptidase (POP) is a serine protease enzymes implicated in PD pathogenesis via an increase in the aggregation of α-synuclein protein in the brain.\u0000\u0000\u0000\u0000This study aims to identify potent anti-PD ligands with inhibitory potential against POP\u0000\u0000\u0000\u0000Ligand-based pharmacophore modeling, Glide extra precision (XP) docking, and post-simulation analysis methods were used.\u0000\u0000\u0000\u0000The adopted ligand-based (LB) modeling generated pharmacophoric features, including 1 hydrophobic group, 1 positive ionizable group, 2 aromatic rings, and 2 hydrogen bond acceptors. A total of 23 hits with a Gunner-Henry score of 0.7 and an enrichment factor of 30.24 were obtained as validation protocols, making it an ideal model. The LB model retrieved 177 hit compounds from the 69,543 natural screening ligands available in the Interbioscreen database. Interestingly, ligands 1, 2, 3, 4, and 5 orderly demonstrated higher binding affinities with Glide XP docking of -9.0, -8.8, -8.7, -8.7, -8.7 kcal/mol compared to reference drugs, GSK552 and ZPP with -8.2, and -6.8 kcal/mol respectively. Similarly, their MM/GBSA values were recorded as -54.4, -51.3, -58.4, -49.3, - 33.5, & -32.5 kJ/mol respectively. Further, MD analysis indicated that ligands had higher favorable binding and stability to the receptor.\u0000\u0000\u0000\u0000Overall, the study paves the way for developing potential anti-PD therapeutics. The ligands are recommended as adjuvant/single candidate as anti-PD candidates upon further experiment.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87866640","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 : 2023-08-22DOI: 10.2174/1570180820666230822093545
Prabha Thangavelu, Ramasamy Ganesan, Kuduva Gurumoorthy Premkumar, S. Thangavelu, Selvinthanuja Chellappa, L. Vivekanandan, R. Veerasamy, Pradeep Kumar M.R.
Background: The co-infection of HIV and abdominal TB poses a worldwide danger to humanity. This is because there are more strains of bacteria that are resistant to many classes of currently available medications. According to current findings, repurposing existing available medications will result in more effective functioning than using newly designed medications. Based on this fact, we hypothesised that the PI could be repurposed; we used Food and Drug Administration (FDA)-approved PI drugs to treat HIV co-infected patients with abdominal TB, and a computational study has been conducted. This comprises network analysis models to find their protein drug interaction (PDI) through a search tool for interacting chemicals (STICH) module of Cytoscape network analysis model followed by the screening of these drugs for their ADMET prediction and binding affinity with adenosine deaminase (ADA), a protein responsible for abdominal TB, and the HIV-1 Nef protein, responsible for the regulation of immune function (CD4+). The network analysis showed 13 nearest binding drugs of these proteins of interest. The ADMET study result showed the pharmacologically relevant parameters that have a significant effect on the binding affinity, bioavailability, and toxicity of PI. The top three scores achieved by PI against adenosine deaminase enzyme activity (PDB ID: 1A4M) are viz., -23.7919, -23.3529, and -22.6773 for Ritonavir, Tipranavir, and Atazanavir, respectively. The top three scores achieved by PI against HIV-1 Nef protein activity (PDB ID: 6URI) are viz., -28.7321, -28.4987, and -28.3155 for Atazanavir, Tipranavir, and Simeprevir, respectively. The active site of ADA and HIV-1 Nef proteins comprises amino acid residues such as for Tipranavir: Arene-Cation interaction (Phenyl and Pyridine)- Arg B1081, and Lys B1033 (1A4M) and Arene-Cation interaction (Pyridine and Phenyl)- Lys D11 and Arg D33; Sidechain acceptor Thr B40; Sidechain donor- Asp D30; Backbone donor- Ala B37 (6URI). Atazanavir: Arene-Cation interaction (Phenyl)- Lys A254 and Lys B1033; Sidechain acceptor - Arg A251 (1A4M). Thus, from the computational studies carried out, we could obtain hints for optimising the molecular selectivity of the PI to provide help in the design of new compounds via the repurposing strategy of the FDA-approved PI for effective treatment of co-morbidity with HIV and abdominal TB. However, further pharmacokinetics, pharmacodynamics, preclinical, and clinical studies permit the design of the new agents without undesirable interactions.
{"title":"Targeting ADA and HIV-1 Nef Protein with Protease Inhibitors: a Repurposing Strategy through Molecular Networking and an in silico Approach for Integrated Management of HIV Co-infected with Abdominal Tuberculosis","authors":"Prabha Thangavelu, Ramasamy Ganesan, Kuduva Gurumoorthy Premkumar, S. Thangavelu, Selvinthanuja Chellappa, L. Vivekanandan, R. Veerasamy, Pradeep Kumar M.R.","doi":"10.2174/1570180820666230822093545","DOIUrl":"https://doi.org/10.2174/1570180820666230822093545","url":null,"abstract":"\u0000\u0000Background: The co-infection of HIV and abdominal TB poses a worldwide danger to humanity. This is because there are more strains of bacteria that are resistant to many classes of currently available medications. According to current findings, repurposing existing available medications will result in more effective functioning than using newly designed medications.\u0000\u0000\u0000\u0000Based on this fact, we hypothesised that the PI could be repurposed; we used Food and Drug Administration (FDA)-approved PI drugs to treat HIV co-infected patients with abdominal TB, and a computational study has been conducted.\u0000\u0000\u0000\u0000This comprises network analysis models to find their protein drug interaction (PDI) through a search tool for interacting chemicals (STICH) module of Cytoscape network analysis model followed by the screening of these drugs for their ADMET prediction and binding affinity with adenosine deaminase (ADA), a protein responsible for abdominal TB, and the HIV-1 Nef protein, responsible for the regulation of immune function (CD4+).\u0000\u0000\u0000\u0000The network analysis showed 13 nearest binding drugs of these proteins of interest. The ADMET study result showed the pharmacologically relevant parameters that have a significant effect on the binding affinity, bioavailability, and toxicity of PI. The top three scores achieved by PI against adenosine deaminase enzyme activity (PDB ID: 1A4M) are viz., -23.7919, -23.3529, and -22.6773 for Ritonavir, Tipranavir, and Atazanavir, respectively. The top three scores achieved by PI against HIV-1 Nef protein activity (PDB ID: 6URI) are viz., -28.7321, -28.4987, and -28.3155 for Atazanavir, Tipranavir, and Simeprevir, respectively. The active site of ADA and HIV-1 Nef proteins comprises amino acid residues such as for Tipranavir: Arene-Cation interaction (Phenyl and Pyridine)- Arg B1081, and Lys B1033 (1A4M) and Arene-Cation interaction (Pyridine and Phenyl)- Lys D11 and Arg D33; Sidechain acceptor Thr B40; Sidechain donor- Asp D30; Backbone donor- Ala B37 (6URI). Atazanavir: Arene-Cation interaction (Phenyl)- Lys A254 and Lys B1033; Sidechain acceptor - Arg A251 (1A4M).\u0000\u0000\u0000\u0000Thus, from the computational studies carried out, we could obtain hints for optimising the molecular selectivity of the PI to provide help in the design of new compounds via the repurposing strategy of the FDA-approved PI for effective treatment of co-morbidity with HIV and abdominal TB. However, further pharmacokinetics, pharmacodynamics, preclinical, and clinical studies permit the design of the new agents without undesirable interactions.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77632609","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}
β-Glucosidase has a variety of biological functions. A structural model for a potential β-glucosidase inhibitor has been proposed in the previous studies. A series f new diaryl derivatives linked through benzimidazole have been randomly and rationally designed, synthesized, and evaluated for their inhibitory activities against β-glucosidase (almond). The proposed structural model provides a new strategy for the design of potent β-glucosidase inhibitors. According to the model, a series of benzimidazole derivatives were designed and synthesized, and their inhibitory activity, Ki value, inhibitory type, and binding mode analysis (PDB ID: 2J7C) on β-glucosidase (almond) were evaluated. Two compounds 7b and 7d were the best inhibitors with IC50 values of 7.86 M and 3.52 μM, respectively. Their Ki values were calculated to be 9.91 μM and 5.81 μM, respectively. The SAR analysis suggested that such benzimidazole derivatives might bind to the active site of β-glucosidase mainly through hydrogen bonds on o-trihydroxyphenol; the additional phenyl ring on the other side towards the solvent-exposed region played a very important role in improving their inhibitory activity against β-glucosidase
{"title":"Rational Design and Synthesis of Novel Benzimidazole Derivatives as Potential β-Glucosidase Inhibitors","authors":"Hua Chen, Xu Liu, Ge Sun, Fengxing Li, Xia Feng, Tongguan Jia, Chengyao Luo, Shijie Chen","doi":"10.2174/1570180820666230822141514","DOIUrl":"https://doi.org/10.2174/1570180820666230822141514","url":null,"abstract":"\u0000\u0000β-Glucosidase has a variety of biological functions. A structural model for a potential β-glucosidase inhibitor has been proposed in the previous studies.\u0000\u0000\u0000\u0000A series f new diaryl derivatives linked through benzimidazole have been randomly and rationally designed, synthesized, and evaluated for their inhibitory activities against β-glucosidase (almond). The proposed structural model provides a new strategy for the design of potent β-glucosidase inhibitors.\u0000\u0000\u0000\u0000According to the model, a series of benzimidazole derivatives were designed and synthesized, and their inhibitory activity, Ki value, inhibitory type, and binding mode analysis (PDB ID: 2J7C) on β-glucosidase (almond) were evaluated.\u0000\u0000\u0000\u0000Two compounds 7b and 7d were the best inhibitors with IC50 values of 7.86 M and 3.52 μM, respectively. Their Ki values were calculated to be 9.91 μM and 5.81 μM, respectively.\u0000\u0000\u0000\u0000The SAR analysis suggested that such benzimidazole derivatives might bind to the active site of β-glucosidase mainly through hydrogen bonds on o-trihydroxyphenol; the additional phenyl ring on the other side towards the solvent-exposed region played a very important role in improving their inhibitory activity against β-glucosidase\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85855320","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 : 2023-08-21DOI: 10.2174/1570180820666230821102836
Abdelmoujoud Faris, Ibrahim M. Ibrahim, Souvik Chakraborty, Omkulthom Al kamaly, S. Alshawwa, Menana EL Hallaoui
This study aimed to discover a novel active compound capable of effectively inhibiting JAK3/STAT1 and CYP3A4 using molecular modelling techniques, with the goal of treating autoimmune diseases such as cancer and specifically rheumatoid arthritis. The study involved modelling compounds derived from pyrazolopyrimidine, followed by screening methods to identify the most promising compounds. Moreover, this study seeks to identify potential compounds that can inhibit JAK3/STAT through molecular modelling techniques and validate the stability and affinity of the predicted molecule. Various molecular modelling techniques were employed to identify potential compounds and assess the stability and affinity of the predicted molecule. A pharmacophore hypothesis was developed to obtain crucial information about the experimental series of pyrazolopyrimidine studied, which served as the basis for designing new molecules. Additionally, ADMET was utilized to predict and evaluate the pharmacokinetic properties and potential toxicity of the compound prior to synthesis or utilization. To determine the essential residues involved in the interaction between the molecule and the target JAK3 protein, the covalent docking method was applied. We further validated the binding stability of the JAK3 protein with the ligands ZINC62162141 and Tofacitinib, both of which have been approved by the FDA for JAK3/STAT inhibition., using DFT/B3LYP/6-31G molecular dynamics simulations lasting 1000 ns and MM/GBSA. During the study, we identified compounds that displayed notable activity against JAK3/STAT, specifically those containing thiadiazol, oxadiazol, and chlorophenyl groups. Additionally, the pharmacophore model, ADRRR_1, exhibited promising potential for predicting new molecules. The predicted compound, ZINC62162141, demonstrated favourable ADMET properties, including inhibition of CYP3A4. Furthermore, we assessed its binding stability to the target protein and determined its affinity for the protein-ligand complex using MMGBSA. The results of this study suggest that the compounds identified have the potential to be promising candidates for inhibiting JAK3/STAT and CYP3A4, offering potential therapeutic benefits for the treatment of rheumatoid arthritis. These findings provide a foundation for subsequent experimental validation and the development of novel drugs in this field.
{"title":"Identification of Selective JAK3/STAT1 and CYP34A from Pyrazolopyrimidine Derivatives: A Search for Potential Drug Targets for Rheumatoid Arthritis using In-silico Drug Discovery Techniques","authors":"Abdelmoujoud Faris, Ibrahim M. Ibrahim, Souvik Chakraborty, Omkulthom Al kamaly, S. Alshawwa, Menana EL Hallaoui","doi":"10.2174/1570180820666230821102836","DOIUrl":"https://doi.org/10.2174/1570180820666230821102836","url":null,"abstract":"\u0000\u0000This study aimed to discover a novel active compound capable of effectively inhibiting JAK3/STAT1 and CYP3A4 using molecular modelling techniques, with the goal of treating autoimmune diseases such as cancer and specifically rheumatoid arthritis. The study involved modelling compounds derived from pyrazolopyrimidine, followed by screening methods to identify the most promising compounds. Moreover, this study seeks to identify potential compounds that can inhibit JAK3/STAT through molecular modelling techniques and validate the stability and affinity of the predicted molecule.\u0000\u0000\u0000\u0000Various molecular modelling techniques were employed to identify potential compounds and assess the stability and affinity of the predicted molecule. A pharmacophore hypothesis was developed to obtain crucial information about the experimental series of pyrazolopyrimidine studied, which served as the basis for designing new molecules. Additionally, ADMET was utilized to predict and evaluate the pharmacokinetic properties and potential toxicity of the compound prior to synthesis or utilization. To determine the essential residues involved in the interaction between the molecule and the target JAK3 protein, the covalent docking method was applied. We further validated the binding stability of the JAK3 protein with the ligands ZINC62162141 and Tofacitinib, both of which have been approved by the FDA for JAK3/STAT inhibition., using DFT/B3LYP/6-31G molecular dynamics simulations lasting 1000 ns and MM/GBSA.\u0000\u0000\u0000\u0000During the study, we identified compounds that displayed notable activity against JAK3/STAT, specifically those containing thiadiazol, oxadiazol, and chlorophenyl groups. Additionally, the pharmacophore model, ADRRR_1, exhibited promising potential for predicting new molecules. The predicted compound, ZINC62162141, demonstrated favourable ADMET properties, including inhibition of CYP3A4. Furthermore, we assessed its binding stability to the target protein and determined its affinity for the protein-ligand complex using MMGBSA.\u0000\u0000\u0000\u0000The results of this study suggest that the compounds identified have the potential to be promising candidates for inhibiting JAK3/STAT and CYP3A4, offering potential therapeutic benefits for the treatment of rheumatoid arthritis. These findings provide a foundation for subsequent experimental validation and the development of novel drugs in this field.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79796851","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 : 2023-08-18DOI: 10.2174/1570180820666230818100059
Rui-Jing Fang, Yan-jun Zhang, Wei-Xian Wang, Tianle Wu, Shuai Zhang, Yi He, Fei Xiong, Zhong-hua Wang
Acquired Immunodeficiency Syndrome (AIDS) is one of most prevalent infectious diseases in the world , and HIV-1 protease (PR) is a vital target of drug design. Nowadays, three-dimensional quantitative structure-activity relationships (3D-QSAR) are applied to help design new protease inhibitions (PIs). The primary objective of this study is to apply the 3D-QSAR study to a series of 42 derivatives of Darunavir (DRV) and to design new molecules possessing high antivirus activity. Partial Least Squares (PLS) were used to cross-validate the dataset of compounds, and the optimal number of principal components (ONC), cross-validate coefficient (q²), standard error of estimate (SEE), non-cross-validated correlation coefficient (R²) and fisher test value (F) were calculated to assess model robustness. In this study, the CoMSIA-DAH model (q²=0.754, r²= 0.988, rpred2=0.57) possessed the highest predicted activity. Newly designed molecules were analyzed by docking studies with compound 25 taken as a template. Within eight newly designed drugs, compound N02 possessed the highest antivirus activity (IC50=0.00461 nM) predicted by the CoMSIA-DAH model. The Surflex-Dock module of SYBYL-X 2.0 was used to affirm the predicted anti-PR activity of the newly designed compounds and the results of docking complex structure could be visualized. All newly designed molecules were in agreement with CSore above four and the docking study revealed that Asp29, Asp30, Ile50, Asp124, Asp128, Asp129 and Ile149 were critical residues in the process of inhibiting PR. One of the main aspects of this study is the successful design of a series of molecules with excellent investigatory values, which elucidates explicit quantitative structure-activity relationships of DRV derivatives and will provide significant suggestions for future pharmaceutical research.
{"title":"The 3D-QSAR Study, Molecular Docking, and ADMET Analysis of Darunavir Derivatives of HIV-1 Protease Inhibitors","authors":"Rui-Jing Fang, Yan-jun Zhang, Wei-Xian Wang, Tianle Wu, Shuai Zhang, Yi He, Fei Xiong, Zhong-hua Wang","doi":"10.2174/1570180820666230818100059","DOIUrl":"https://doi.org/10.2174/1570180820666230818100059","url":null,"abstract":"\u0000\u0000Acquired Immunodeficiency Syndrome (AIDS) is one of most prevalent infectious diseases in the world , and HIV-1 protease (PR) is a vital target of drug design. Nowadays, three-dimensional quantitative structure-activity relationships (3D-QSAR) are applied to help design new protease inhibitions (PIs).\u0000\u0000\u0000\u0000The primary objective of this study is to apply the 3D-QSAR study to a series of 42 derivatives of Darunavir (DRV) and to design new molecules possessing high antivirus activity.\u0000\u0000\u0000\u0000Partial Least Squares (PLS) were used to cross-validate the dataset of compounds, and the optimal number of principal components (ONC), cross-validate coefficient (q²), standard error of estimate (SEE), non-cross-validated correlation coefficient (R²) and fisher test value (F) were calculated to assess model robustness. In this study, the CoMSIA-DAH model (q²=0.754, r²= 0.988, rpred2=0.57) possessed the highest predicted activity. Newly designed molecules were analyzed by docking studies with compound 25 taken as a template.\u0000\u0000\u0000\u0000Within eight newly designed drugs, compound N02 possessed the highest antivirus activity (IC50=0.00461 nM) predicted by the CoMSIA-DAH model. The Surflex-Dock module of SYBYL-X 2.0 was used to affirm the predicted anti-PR activity of the newly designed compounds and the results of docking complex structure could be visualized. All newly designed molecules were in agreement with CSore above four and the docking study revealed that Asp29, Asp30, Ile50, Asp124, Asp128, Asp129 and Ile149 were critical residues in the process of inhibiting PR.\u0000\u0000\u0000\u0000One of the main aspects of this study is the successful design of a series of molecules with excellent investigatory values, which elucidates explicit quantitative structure-activity relationships of DRV derivatives and will provide significant suggestions for future pharmaceutical research.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74116113","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 : 2023-08-18DOI: 10.2174/1570180820666230818092456
Wang Jun, Jing-jing Cheng
Modern pharmacological research indicated that Camellia nitidissima (CAM) had significant anti-tumor activity, but the investigation of its mechanism was still lacking. The multi-component, multi-target and multi-pathway mechanism of CAM against tumor was investigated based on network pharmacology and molecular docking. The active ingredients and targets of CAM were selected through a literature search, Traditional Chinese Medicine Systems Pharmacology database and PharmMapper database, and tumor-related targets were selected by GeneCards database, then to obtain the anti-tumor related targets of CAM. The protein interaction relationship was obtained through STRING database, protein-protein interaction network was constructed using Cytoscape 3.7.2 software, and enrichment analysis of GO and KEGG was conducted. AutoDock Tools 1.5.6 software was used to verify the molecular docking between the key ingredients and the key targets. Catechin, epicatechin and luteolin were identified as the key anti-tumor related ingredients, and ESR1, EGFR, MAPK8, MAPK10, AR, PGR, F2 and PIK3CG were identified as the key targets. The GO entries mainly involved metabolic process, cellular process, response to stimulus, organelle, cytosol, etc. The KEGG enrichment showed that the key pathways included pathways in cancer, prostate cancer, pancreatic cancer, breast cancer, estrogen signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, etc. KEGG pathway maps indicated that the anti-tumor effect of CAM may be mainly achieved by intervening related targets in the following pathways: AR-HSP/AR-AR/PSA/proliferation and evading apoptosis; F2/GPCR/…/ROCK/tissue invasion and metastasis; F2/GPCR/…/Raf/MAPK signaling pathway/proliferation and sustained angiogenesis; EGFR/PI3K-Akt signaling pathway/proliferation, evading apoptosis and sustained angiogenesis; EGFR/Grb2/…/Raf/MAPK signaling pathway/proliferation and sustained angiogenesis; ER/Estrogen signaling pathway/proliferation; PR/PR-COR/Wnts-RANKL/proliferation; oxidative stress (.O₂-, .OH, H₂O₂)/KEAP1/NRF2/.../proliferation and evading apoptosis. The results of molecular docking showed that the key active ingredients had a good binding activity with each key target. It was predicted that the main active ingredients of CAM could bind to tumor-related targets, such as receptor and coagulation-promoting factor, scavenge free radicals, and then interfere with the occurrence and development of tumors.
{"title":"Anti-tumor mechanism of Camellia nitidissima based on network pharmacology and molecular docking","authors":"Wang Jun, Jing-jing Cheng","doi":"10.2174/1570180820666230818092456","DOIUrl":"https://doi.org/10.2174/1570180820666230818092456","url":null,"abstract":"\u0000\u0000Modern pharmacological research indicated that Camellia nitidissima (CAM) had significant anti-tumor activity, but the investigation of its mechanism was still lacking.\u0000\u0000\u0000\u0000The multi-component, multi-target and multi-pathway mechanism of CAM against tumor was investigated based on network pharmacology and molecular docking.\u0000\u0000\u0000\u0000The active ingredients and targets of CAM were selected through a literature search, Traditional Chinese Medicine Systems Pharmacology database and PharmMapper database, and tumor-related targets were selected by GeneCards database, then to obtain the anti-tumor related targets of CAM. The protein interaction relationship was obtained through STRING database, protein-protein interaction network was constructed using Cytoscape 3.7.2 software, and enrichment analysis of GO and KEGG was conducted. AutoDock Tools 1.5.6 software was used to verify the molecular docking between the key ingredients and the key targets.\u0000\u0000\u0000\u0000Catechin, epicatechin and luteolin were identified as the key anti-tumor related ingredients, and ESR1, EGFR, MAPK8, MAPK10, AR, PGR, F2 and PIK3CG were identified as the key targets. The GO entries mainly involved metabolic process, cellular process, response to stimulus, organelle, cytosol, etc. The KEGG enrichment showed that the key pathways included pathways in cancer, prostate cancer, pancreatic cancer, breast cancer, estrogen signaling pathway, MAPK signaling pathway, PI3K-Akt signaling pathway, etc. KEGG pathway maps indicated that the anti-tumor effect of CAM may be mainly achieved by intervening related targets in the following pathways: AR-HSP/AR-AR/PSA/proliferation and evading apoptosis; F2/GPCR/…/ROCK/tissue invasion and metastasis; F2/GPCR/…/Raf/MAPK signaling pathway/proliferation and sustained angiogenesis; EGFR/PI3K-Akt signaling pathway/proliferation, evading apoptosis and sustained angiogenesis; EGFR/Grb2/…/Raf/MAPK signaling pathway/proliferation and sustained angiogenesis; ER/Estrogen signaling pathway/proliferation; PR/PR-COR/Wnts-RANKL/proliferation; oxidative stress (.O₂-, .OH, H₂O₂)/KEAP1/NRF2/.../proliferation and evading apoptosis. The results of molecular docking showed that the key active ingredients had a good binding activity with each key target.\u0000\u0000\u0000\u0000It was predicted that the main active ingredients of CAM could bind to tumor-related targets, such as receptor and coagulation-promoting factor, scavenge free radicals, and then interfere with the occurrence and development of tumors.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91365436","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 : 2023-08-18DOI: 10.2174/1570180820666230818140501
A. Hafid, D. Sari, F. Y. Wardana, Mohammad Rizki Fadhil Pratama, L. Tumewu, Hilkatul Ilmi, A. A. Permanasari, Hanifah Khairun Nisa, A. Widyawaruyanti
Amoebiasis is caused by Entamoeba histolytica, a pathogenic species living on human colon tissues. Metronidazole is currently used for the treatment of amoebiasis, but resistance of E. histolytica to the use of such treatment has been reported. Therefore, the development of new anti-amoebic drugs is still very much needed for clinical treatment. Preliminary research on extract and fractions from Cratoxylum sumatranum stem bark has shown their anti-amoebic activity. Two compounds from the cage xanthone groups, cochinchinoxanthone and cochinchinone D, have been isolated from the active fraction of C. sumatranum stem bark. This study aimed to investigate the anti-amoebic activity of the two known compounds against E. histolytica. The in silico method used was molecular docking with several receptors, including thioredoxin reductase, triose phosphate isomerase, pyruvate ferredoxin oxidoreductase, Giardia fructose-1,6-bisphosphate aldolase, serine acetyltransferase, and phosphoserine phosphatase. The prediction of ADMET properties was also carried out for both the compounds. The results showed cochinchinone D to have a higher binding affinity to thioredoxin reductase, pyruvate ferredoxin oxidoreductase, and Giardia fructose-1,6-bisphosphate aldolase receptors than cochinchinoxanthone. In contrast, cochinchinoxanthone bound better to the triose phosphate isomerase and phosphoserine phosphatase receptors, while both exhibited the same affinity for serine acetyltransferase. In general, the two compounds were also found to have similar ADMET profiles. In conclusion, caged xanthone compounds from C. sumatranum have the potential to be developed as anti-amoebic agents against E. histolytica through the mechanism of inhibition of these enzymes.
{"title":"In Silico Investigation of Caged Xanthone Compounds Isolated from Cratoxylum sumatranum Stem Bark Against Entamoeba histolytica Enzymes","authors":"A. Hafid, D. Sari, F. Y. Wardana, Mohammad Rizki Fadhil Pratama, L. Tumewu, Hilkatul Ilmi, A. A. Permanasari, Hanifah Khairun Nisa, A. Widyawaruyanti","doi":"10.2174/1570180820666230818140501","DOIUrl":"https://doi.org/10.2174/1570180820666230818140501","url":null,"abstract":"\u0000\u0000Amoebiasis is caused by Entamoeba histolytica, a pathogenic species living on human colon tissues. Metronidazole is currently used for the treatment of amoebiasis, but resistance of E. histolytica to the use of such treatment has been reported. Therefore, the development of new anti-amoebic drugs is still very much needed for clinical treatment. Preliminary research on extract and fractions from Cratoxylum sumatranum stem bark has shown their anti-amoebic activity. Two compounds from the cage xanthone groups, cochinchinoxanthone and cochinchinone D, have been isolated from the active fraction of C. sumatranum stem bark.\u0000\u0000\u0000\u0000This study aimed to investigate the anti-amoebic activity of the two known compounds against E. histolytica.\u0000\u0000\u0000\u0000The in silico method used was molecular docking with several receptors, including thioredoxin reductase, triose phosphate isomerase, pyruvate ferredoxin oxidoreductase, Giardia fructose-1,6-bisphosphate aldolase, serine acetyltransferase, and phosphoserine phosphatase. The prediction of ADMET properties was also carried out for both the compounds.\u0000\u0000\u0000\u0000The results showed cochinchinone D to have a higher binding affinity to thioredoxin reductase, pyruvate ferredoxin oxidoreductase, and Giardia fructose-1,6-bisphosphate aldolase receptors than cochinchinoxanthone. In contrast, cochinchinoxanthone bound better to the triose phosphate isomerase and phosphoserine phosphatase receptors, while both exhibited the same affinity for serine acetyltransferase. In general, the two compounds were also found to have similar ADMET profiles.\u0000\u0000\u0000\u0000In conclusion, caged xanthone compounds from C. sumatranum have the potential to be developed as anti-amoebic agents against E. histolytica through the mechanism of inhibition of these enzymes.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"76804710","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 : 2023-08-17DOI: 10.2174/1570180820666230817101819
D. Megawati, J. Ekowati, Siswandono Siswodihardjo
N-benzoyl-N'-naphthylthiourea (BNTU) is a thiourea-derived compound that is predicted to have anti-breast cancer activity. However, their physicochemical properties, ADMET, and receptor-specific targets for their anti-breast cancer activity have not been reported. Objective: This study aimed to predict the physicochemical properties, ADMET, and anti-breast cancer activity of BNTU and its derivatives by in silico approach. The physicochemical and ADMET properties were predicted using the pkCSM online program and ProTox-II online tool. While the anti-breast cancer activity was predicted using the molecular docking method through the Molegro Virtual Docker (MVD) program on the HER-2 receptor. The parameter observed in the molecular docking method was the bond energy value or rerank score (RS). Compounds with small RS values were predicted to have a great activity. Most BNTU derivatives had lower RS values than BNTU, especially 4TBBNTU, and 4CFBNTU, although their RS values were still higher than lapatinib and TAK-285. As for the reference ligand hydroxyurea, the RS value of BNTU and its derivatives was much lower. The physicochemical and pharmacokinetic properties (ADMET) of lapatinib and TAK-285 were not better than that of BNTU and its derivatives. Five compounds that deserve to be synthesized and tested for anti-breast cancer activity in vitro and in vivo are 4TBBNTU, 3CFBNTU, 4CFBNTU, 4OCBNTU, and the lead compound
n -苯甲酰-n '-萘基硫脲(BNTU)是一种硫脲衍生化合物，预计具有抗乳腺癌活性。然而，它们的理化性质、ADMET和抗乳腺癌活性的受体特异性靶点尚未报道。目的:采用计算机模拟方法预测BNTU及其衍生物的理化性质、ADMET及抗乳腺癌活性。利用pkCSM在线程序和ProTox-II在线工具预测了其理化性质和ADMET性质。通过Molegro虚拟Docker (MVD)程序对HER-2受体进行分子对接，预测其抗乳腺癌活性。在分子对接方法中观察到的参数为键能值或重秩评分(RS)。预测RS值小的化合物具有较高的活性。大多数BNTU衍生物的RS值低于BNTU，尤其是4TBBNTU和4CFBNTU，尽管它们的RS值仍高于拉帕替尼和TAK-285。对于参考配体羟基脲，BNTU及其衍生物的RS值要低得多。拉帕替尼和TAK-285的理化药代动力学性质(ADMET)均不优于BNTU及其衍生物。值得合成并在体外和体内进行抗乳腺癌活性测试的化合物有4TBBNTU、3CFBNTU、4CFBNTU、4OCBNTU和先导化合物
{"title":"Physicochemical, ADMET Properties, and Molecular Docking Studies of N-Benzoyl-N’-Naphtylthiourea Derivatives for Anti-Breast Cancer Activity","authors":"D. Megawati, J. Ekowati, Siswandono Siswodihardjo","doi":"10.2174/1570180820666230817101819","DOIUrl":"https://doi.org/10.2174/1570180820666230817101819","url":null,"abstract":"\u0000\u0000N-benzoyl-N'-naphthylthiourea (BNTU) is a thiourea-derived compound that is predicted to have anti-breast cancer activity. However, their physicochemical properties, ADMET, and receptor-specific targets for their anti-breast cancer activity have not been reported.\u0000Objective: This study aimed to predict the physicochemical properties, ADMET, and anti-breast cancer activity of BNTU and its derivatives by in silico approach.\u0000\u0000\u0000\u0000The physicochemical and ADMET properties were predicted using the pkCSM online program and ProTox-II online tool. While the anti-breast cancer activity was predicted using the molecular docking method through the Molegro Virtual Docker (MVD) program on the HER-2 receptor. The parameter observed in the molecular docking method was the bond energy value or rerank score (RS). Compounds with small RS values were predicted to have a great activity.\u0000\u0000\u0000\u0000Most BNTU derivatives had lower RS values than BNTU, especially 4TBBNTU, and 4CFBNTU, although their RS values were still higher than lapatinib and TAK-285. As for the reference ligand hydroxyurea, the RS value of BNTU and its derivatives was much lower. The physicochemical and pharmacokinetic properties (ADMET) of lapatinib and TAK-285 were not better than that of BNTU and its derivatives.\u0000\u0000\u0000\u0000Five compounds that deserve to be synthesized and tested for anti-breast cancer activity in vitro and in vivo are 4TBBNTU, 3CFBNTU, 4CFBNTU, 4OCBNTU, and the lead compound\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91107589","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 : 2023-08-16DOI: 10.2174/1570180820666230816141241
Paula Alvarez Abreu, Caroline Reis Santiago Paschoal, Vitor Won-Held Rabelo, Tamillis Figueiredo de Oliveira
Chagas disease is a neglected disease caused by the protozoan Trypanosoma cruzi that affects 7 million people worldwide. The current treatment is limited due to safety and efficacy issues. Therefore, the search for new antiparasitic drugs is fundamental. The enzyme squalene synthase (SQS) is an attractive therapeutic target since it participates in the ergosterol biosynthesis pathway. In the present study, we explored the Brazilian biodiversity to search for potential inhibitors of T. cruzi SQS (TcSQS) using ligand and structure-based virtual screening strategies. A virtual screening was performed within the NUBBE database, with more than 2,200 natural products (NP) or semisynthetic derivatives from the Brazilian biodiversity. Molecular docking and ADMET predictions were then performed. A set of 12 NP showed interactions with TcSQS like those observed by known inhibitors and shared literature evidence that supports the predicted activity. Three compounds (flavonoids) showed good ADMET properties as potential inhibitors of TcSQS.
{"title":"Exploring Brazilian Natural Products as Potential Bioactive Compounds against Trypanosoma cruzi by targeting Squalene Synthase","authors":"Paula Alvarez Abreu, Caroline Reis Santiago Paschoal, Vitor Won-Held Rabelo, Tamillis Figueiredo de Oliveira","doi":"10.2174/1570180820666230816141241","DOIUrl":"https://doi.org/10.2174/1570180820666230816141241","url":null,"abstract":"\u0000\u0000Chagas disease is a neglected disease caused by the protozoan Trypanosoma cruzi that affects 7 million people worldwide. The current treatment is limited due to safety and efficacy issues. Therefore, the search for new antiparasitic drugs is fundamental. The enzyme squalene synthase (SQS) is an attractive therapeutic target since it participates in the ergosterol biosynthesis pathway.\u0000\u0000\u0000\u0000In the present study, we explored the Brazilian biodiversity to search for potential inhibitors of T. cruzi SQS (TcSQS) using ligand and structure-based virtual screening strategies.\u0000\u0000\u0000\u0000A virtual screening was performed within the NUBBE database, with more than 2,200 natural products (NP) or semisynthetic derivatives from the Brazilian biodiversity. Molecular docking and ADMET predictions were then performed.\u0000\u0000\u0000\u0000A set of 12 NP showed interactions with TcSQS like those observed by known inhibitors and shared literature evidence that supports the predicted activity.\u0000\u0000\u0000\u0000Three compounds (flavonoids) showed good ADMET properties as potential inhibitors of TcSQS.\u0000","PeriodicalId":18063,"journal":{"name":"Letters in Drug Design & Discovery","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79338026","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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