Pub Date : 2023-09-15DOI: 10.2174/1570180820666230915140653
Yasir Nawaz, Javaria Zafar, Abdul Basit Ashfaq, Fouzia Tanvir, Asma Umar, Imran Majeed Khan, Sadaf Ambreen
to explore diseases in pakistani people Cataract is a non-communicable eye disease worldwide, with the greatest number of patients in middle and low income nations. The study aimed to find the association of socioeconomic status of cataract patients in Pakistani population A survey based study was performed to collect questionnaire based Performa to collect relevant information from patients by the relevant consent form under the declaration of Helsinki. It was observed that 46.05% males and 53.95 The socioeconomic status including illiteracy rate, cast status, gender and age difference and occupation status of people are associated with the development of cataract none
{"title":"The occurrence and association of socio-economic status of age-related cataract among Pakistani patients","authors":"Yasir Nawaz, Javaria Zafar, Abdul Basit Ashfaq, Fouzia Tanvir, Asma Umar, Imran Majeed Khan, Sadaf Ambreen","doi":"10.2174/1570180820666230915140653","DOIUrl":"https://doi.org/10.2174/1570180820666230915140653","url":null,"abstract":"to explore diseases in pakistani people\u0000\u0000\u0000\u0000Cataract is a non-communicable eye disease worldwide, with the greatest number of patients in middle and low income nations.\u0000\u0000\u0000\u0000The study aimed to find the association of socioeconomic status of cataract patients in Pakistani population\u0000\u0000\u0000\u0000A survey based study was performed to collect questionnaire based Performa to collect relevant information from patients by the relevant consent form under the declaration of Helsinki.\u0000\u0000\u0000\u0000It was observed that 46.05% males and 53.95\u0000\u0000\u0000\u0000The socioeconomic status including illiteracy rate, cast status, gender and age difference and occupation status of people are associated with the development of cataract\u0000\u0000\u0000\u0000none","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"59 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135487507","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 : 2023-09-14DOI: 10.2174/1570180820666230914104206
Yue-zi Wei, Mei-zhu Yang, Wei Yuan
Background: Lung cancer is the malignancy with the second highest diagnostic rate and the leading cause of cancer-related death. Objective: This study aims to investigate the potential mechanism and molecular targets of Panax notoginseng saponins (PNS) in inhibiting lung cancer through network pharmacology. Methods: Pharmacodynamic targets of each compound of PNS were searched from TargetNet, SwissTargetPrediction, and BatMan-TCM databases. Next, the differential expression genes (DEGs) in lung cancer were obtained from the Gene Expression Omnibus (GEO) database and screened by R package. Later, the STRING 11.0 database was utilized to analyze the protein-protein interaction (PPI) network of common targets of PNS-lung cancer, clusterProfiler to perform gene ontology (GO) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the common targets, and Cytoscape 3.8.0 to construct and analyze the "ingredient-target" network for the common targets of PNS-lung cancer. Results: A total of 154 potential pharmacodynamic targets of PNS, 2399 DEGs of lung cancer-related diseases, and 21 common targets of PNS-lung cancer were obtained by database search and screening. The 21 common targets were mainly involved in biological processes (such as small molecule metabolism and cytokine production) and were major components of cellular structures (such as neuronal cell bodies and membrane rafts). Besides, these targets could function as carboxylic ester hydrolases, G protein-coupled amine receptors, and oxidoreductase. They were mainly enriched in 14 signaling pathways, like neuroactive ligand-receptor interaction, regulation of lipolysis in adipocytes, and calcium signaling pathway. Furthermore, the molecular docking results revealed that aldo-keto reductase family 1 member C3 (AKR1C3) and melanin metabolic enzyme (MME) may be direct targets of ginsenoside Rg1 and notoginsenoside R2. Conclusion: Our study showed that ginsenosides inhibit the progression of lung cancer through multiple targets and pathways. More importantly, PNS may treat lung cancer by directly inhibiting AKR1C3.
背景:肺癌是诊断率第二高的恶性肿瘤，也是癌症相关死亡的主要原因。目的:通过网络药理学研究三七皂苷(PNS)抑制肺癌的潜在机制和分子靶点。方法:从TargetNet、SwissTargetPrediction和BatMan-TCM数据库中检索PNS各化合物的药效学靶点。其次，从Gene expression Omnibus (GEO)数据库中获取肺癌差异表达基因(DEGs)，并通过R package进行筛选。随后，利用STRING 11.0数据库分析pns -肺癌共同靶点的蛋白-蛋白相互作用(PPI)网络，利用clusterProfiler进行基因本体(GO)标注，对共同靶点进行京都基因与基因组百科(KEGG)通路富集分析，利用Cytoscape 3.8.0构建并分析pns -肺癌共同靶点的“成分-靶点”网络。结果:通过数据库检索筛选，共获得PNS潜在药效学靶点154个，肺癌相关疾病药效学靶点2399个，PNS-肺癌常见靶点21个。21种常见靶点主要参与生物过程(如小分子代谢和细胞因子产生)，是细胞结构(如神经元细胞体和膜筏)的主要组成部分。此外，这些靶点可能具有羧酸酯水解酶、G蛋白偶联胺受体和氧化还原酶的功能。主要富集于神经活性配体-受体相互作用、调节脂肪细胞脂解、钙信号通路等14条信号通路。此外，分子对接结果显示，醛酮还原酶家族1成员C3 (AKR1C3)和黑色素代谢酶(MME)可能是人参皂苷Rg1和三七皂苷R2的直接作用靶点。结论:我们的研究表明，人参皂苷通过多种靶点和途径抑制肺癌的进展。更重要的是，PNS可能通过直接抑制AKR1C3来治疗肺癌。
{"title":"Network Pharmacological Study of the Active Ingredient of Panax Notoginseng Saponins for the Treatment of Lung Cancer by Inhibiting AKR1C3","authors":"Yue-zi Wei, Mei-zhu Yang, Wei Yuan","doi":"10.2174/1570180820666230914104206","DOIUrl":"https://doi.org/10.2174/1570180820666230914104206","url":null,"abstract":"Background: Lung cancer is the malignancy with the second highest diagnostic rate and the leading cause of cancer-related death. Objective: This study aims to investigate the potential mechanism and molecular targets of Panax notoginseng saponins (PNS) in inhibiting lung cancer through network pharmacology. Methods: Pharmacodynamic targets of each compound of PNS were searched from TargetNet, SwissTargetPrediction, and BatMan-TCM databases. Next, the differential expression genes (DEGs) in lung cancer were obtained from the Gene Expression Omnibus (GEO) database and screened by R package. Later, the STRING 11.0 database was utilized to analyze the protein-protein interaction (PPI) network of common targets of PNS-lung cancer, clusterProfiler to perform gene ontology (GO) annotation, and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis for the common targets, and Cytoscape 3.8.0 to construct and analyze the \"ingredient-target\" network for the common targets of PNS-lung cancer. Results: A total of 154 potential pharmacodynamic targets of PNS, 2399 DEGs of lung cancer-related diseases, and 21 common targets of PNS-lung cancer were obtained by database search and screening. The 21 common targets were mainly involved in biological processes (such as small molecule metabolism and cytokine production) and were major components of cellular structures (such as neuronal cell bodies and membrane rafts). Besides, these targets could function as carboxylic ester hydrolases, G protein-coupled amine receptors, and oxidoreductase. They were mainly enriched in 14 signaling pathways, like neuroactive ligand-receptor interaction, regulation of lipolysis in adipocytes, and calcium signaling pathway. Furthermore, the molecular docking results revealed that aldo-keto reductase family 1 member C3 (AKR1C3) and melanin metabolic enzyme (MME) may be direct targets of ginsenoside Rg1 and notoginsenoside R2. Conclusion: Our study showed that ginsenosides inhibit the progression of lung cancer through multiple targets and pathways. More importantly, PNS may treat lung cancer by directly inhibiting AKR1C3.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"27 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134970677","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 : 2023-09-14DOI: 10.2174/1570180820666230914114446
Diksha Choudhary, Rajwinder Kaur, Bhupinder Kumar
Abstract: Depression is a severe mental disorder characterized by a major imbalance between the levels of neurotransmitters. US11534436 B2 discloses an efficient amount of µ-opioid receptor agonists or their pharmaceutically acceptable salt for efficient treatment of depression. The patent discloses a few new compounds among which compounds 1, 2, 3, 4, and 5 as well as derivatives of basic nucleus A have good µ-opioid receptor agonist activity without risks of opioid addiction or development of addiction withdrawal symptoms. The compounds displayed Emax of 5% to 45% in a GTPγS binding assay while one of the derivatives displayed Emax of 15% to 35% in a GTPγS binding assay. The patent further discloses different embodiments with different potentials. The administration of an effective dose in rats resulted in 125% to 300% efflux of dopamine of baseline. At a dosage of 1-10 mg/kg, the embodiments do not diminish the thermal pain in rodents. Although the patent explored new µ-opioid receptor agonists for the treatment of depressive symptoms, the exhaustive evaluation of toxicity and further mechanisms need to be explored via in vivo models.
{"title":"Morphine-like Novel Compounds for the Treatment of Depressive Symptoms","authors":"Diksha Choudhary, Rajwinder Kaur, Bhupinder Kumar","doi":"10.2174/1570180820666230914114446","DOIUrl":"https://doi.org/10.2174/1570180820666230914114446","url":null,"abstract":"Abstract: Depression is a severe mental disorder characterized by a major imbalance between the levels of neurotransmitters. US11534436 B2 discloses an efficient amount of µ-opioid receptor agonists or their pharmaceutically acceptable salt for efficient treatment of depression. The patent discloses a few new compounds among which compounds 1, 2, 3, 4, and 5 as well as derivatives of basic nucleus A have good µ-opioid receptor agonist activity without risks of opioid addiction or development of addiction withdrawal symptoms. The compounds displayed Emax of 5% to 45% in a GTPγS binding assay while one of the derivatives displayed Emax of 15% to 35% in a GTPγS binding assay. The patent further discloses different embodiments with different potentials. The administration of an effective dose in rats resulted in 125% to 300% efflux of dopamine of baseline. At a dosage of 1-10 mg/kg, the embodiments do not diminish the thermal pain in rodents. Although the patent explored new µ-opioid receptor agonists for the treatment of depressive symptoms, the exhaustive evaluation of toxicity and further mechanisms need to be explored via in vivo models.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"35 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134912225","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 : 2023-09-12DOI: 10.2174/1570180820666230912161923
Ibukun John Abulude, Daniel E Kadouri, Xianwu Guo
Abstract: The increase in multi-drug resistant (MDR) pathogens and the decline in the number of new antibiotics in the production pipeline pose a serious threat to our ability to treat infectious diseases. In this new landscape, once treatable diseases are now potentially life-threatening. This impending danger requires that urgent attention should be given to developing alternative strategies for combating MDR bacteria. A novel alternative is the use of predatory bacteria, B. bacteriovorus spp, that naturally prey on Gram-negative bacteria, including MDR Enterobacteriaceae. B. bacteriovorus has been shown to be non-pathogenic in animal models and on human cell lines, supporting its feasibility to be used to treat infections in animals and possibly humans. This document reviews various aspects of B. bacteriovorus biology, including its unique life cycle, "predatory toolbox", prey range, and recent research advances exploring B. bacteriovorus as an antimicrobial agent, stepping towards its use in human therapy. We also discuss the advantages and limitations of using B. bacteriovorus therapy and the strategies to overcome these limitations.
{"title":"Bdellovibrio bacteriovorus therapy, an emerging alternative to antibiotics","authors":"Ibukun John Abulude, Daniel E Kadouri, Xianwu Guo","doi":"10.2174/1570180820666230912161923","DOIUrl":"https://doi.org/10.2174/1570180820666230912161923","url":null,"abstract":"Abstract: The increase in multi-drug resistant (MDR) pathogens and the decline in the number of new antibiotics in the production pipeline pose a serious threat to our ability to treat infectious diseases. In this new landscape, once treatable diseases are now potentially life-threatening. This impending danger requires that urgent attention should be given to developing alternative strategies for combating MDR bacteria. A novel alternative is the use of predatory bacteria, B. bacteriovorus spp, that naturally prey on Gram-negative bacteria, including MDR Enterobacteriaceae. B. bacteriovorus has been shown to be non-pathogenic in animal models and on human cell lines, supporting its feasibility to be used to treat infections in animals and possibly humans. This document reviews various aspects of B. bacteriovorus biology, including its unique life cycle, \"predatory toolbox\", prey range, and recent research advances exploring B. bacteriovorus as an antimicrobial agent, stepping towards its use in human therapy. We also discuss the advantages and limitations of using B. bacteriovorus therapy and the strategies to overcome these limitations.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"41 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135885277","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 : 2023-09-11DOI: 10.2174/1570180820666230905112912
Xiaopeng Wei, Zhan Jin, Zheqi Fan, Ying Chen, Weikai Jing, Man Zhang, Chunchun Gan, Jinrong Yang
Aim: Major depression and anxiety have increased significantly worldwide since the 2019 outbreak of COVID-19. The development of highly effective antidepressants with low side effects is attracting researchers. Methods: Monoamine oxidase A (MAO-A) is a key enzyme that catalyzes the metabolism of norepinephrine (NE), dopamine (DA), and serotonin (5-HT), etc. Elevated level of MAO-A would lead to increased metabolism of its substrates, thereby causing a decrease in the levels of these neurotransmitter monoamines in the brain leading to depression. Consequently, inhibition of MAO-A was thought to be an effective strategy, as this would treat the root cause of depression. Results and Discussion: Based on the crystal structure of MAO-A, 4 star-hits, as potential MAO-A inhibitors was screened from the compound libraries with central nervous system (CNS) activity by using various computational techniques. Molecular dynamics simulation was used to verify the stability of the ligand- receptor complexes. Conclusion: Furthermore, the ADMET (absorption, distribution, metabolism, excretion and toxicity properties) of the virtual hits were predicted in order to evaluate their lead-like properties and safety. This work provides ideas for the drugs discovery of antidepressant.
{"title":"Discovery of MAO-A Inhibitors as Antidepressant Based on Virtual Screening","authors":"Xiaopeng Wei, Zhan Jin, Zheqi Fan, Ying Chen, Weikai Jing, Man Zhang, Chunchun Gan, Jinrong Yang","doi":"10.2174/1570180820666230905112912","DOIUrl":"https://doi.org/10.2174/1570180820666230905112912","url":null,"abstract":"Aim: Major depression and anxiety have increased significantly worldwide since the 2019 outbreak of COVID-19. The development of highly effective antidepressants with low side effects is attracting researchers. Methods: Monoamine oxidase A (MAO-A) is a key enzyme that catalyzes the metabolism of norepinephrine (NE), dopamine (DA), and serotonin (5-HT), etc. Elevated level of MAO-A would lead to increased metabolism of its substrates, thereby causing a decrease in the levels of these neurotransmitter monoamines in the brain leading to depression. Consequently, inhibition of MAO-A was thought to be an effective strategy, as this would treat the root cause of depression. Results and Discussion: Based on the crystal structure of MAO-A, 4 star-hits, as potential MAO-A inhibitors was screened from the compound libraries with central nervous system (CNS) activity by using various computational techniques. Molecular dynamics simulation was used to verify the stability of the ligand- receptor complexes. Conclusion: Furthermore, the ADMET (absorption, distribution, metabolism, excretion and toxicity properties) of the virtual hits were predicted in order to evaluate their lead-like properties and safety. This work provides ideas for the drugs discovery of antidepressant.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"36 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136026988","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 : 2023-09-11DOI: 10.2174/1570180820666230911165225
Fahad Hassan Shah, Young Seok Eom, Song Ja Kim
Introduction: Charcot Marie Tooth Disease-2 is a debilitating neurogenetic disorder that adversely affects peripheral neurons by disrupting mitochondrial activity. Mutated mitofusin-2 (MFN) is the main culprit behind disruptive mitochondrial function and is considered a therapeutic target in identifying drugs for treating this disease. This disease has no therapeutic medication except for supportive care. Objective: The objective of the current study is to evaluate high-affinity medicinal compounds for mutated MFN-2 and describe their absorption, distribution, metabolism, excretion, and toxic attributes (ADMET). Methods: For ADMET properties, 2,219 medicinal compounds were analyzed with AutoDock Vina using PyRX 0.9 software against MFN-2, SwissADME, and GUSAR. Results: Results from screening studies revealed that three compounds (Liriodenine, Pinocembrin, and Vestitol) show an affinity for amino acids present in the predicted active interface of the MFN-2 protein. Moreover, these compounds render low toxicity and efficient ADME qualities, combined with blood-brain barrier permeability, drug-likeness, and lead-likeness. Conclusion: Liriodenine, pinocembrin and vestitol are therapeutic compounds for CMT-2 treatment and should be used in further in-vitro studies to confirm the results of this research.
Charcot Marie Tooth Disease-2是一种衰弱的神经遗传疾病，通过破坏线粒体活性对周围神经元产生不利影响。有丝分裂蛋白-2 (MFN)突变是线粒体功能破坏的罪魁祸首，被认为是确定治疗这种疾病的药物的治疗靶点。除了支持性护理外，这种疾病没有治疗药物。目的:本研究的目的是评估突变MFN-2的高亲和力药物化合物，并描述它们的吸收、分布、代谢、排泄和毒性属性(ADMET)。方法:使用AutoDock Vina软件，利用PyRX 0.9软件对2219种药物化合物进行抗MFN-2、SwissADME和GUSAR的性质分析。结果:筛选研究结果显示，三种化合物(Liriodenine, Pinocembrin和Vestitol)对MFN-2蛋白预测活性界面上的氨基酸具有亲和力。此外，这些化合物具有低毒性和高效的ADME特性，并具有血脑屏障渗透性、药物相似性和铅相似性。结论:Liriodenine、pinocembrin和vestitol是治疗CMT-2的治疗性化合物，需要进一步的体外研究来证实本研究的结果。
{"title":"Discovering Drug Candidates for Charcot Marie Tooth Disease Type-2","authors":"Fahad Hassan Shah, Young Seok Eom, Song Ja Kim","doi":"10.2174/1570180820666230911165225","DOIUrl":"https://doi.org/10.2174/1570180820666230911165225","url":null,"abstract":"Introduction: Charcot Marie Tooth Disease-2 is a debilitating neurogenetic disorder that adversely affects peripheral neurons by disrupting mitochondrial activity. Mutated mitofusin-2 (MFN) is the main culprit behind disruptive mitochondrial function and is considered a therapeutic target in identifying drugs for treating this disease. This disease has no therapeutic medication except for supportive care. Objective: The objective of the current study is to evaluate high-affinity medicinal compounds for mutated MFN-2 and describe their absorption, distribution, metabolism, excretion, and toxic attributes (ADMET). Methods: For ADMET properties, 2,219 medicinal compounds were analyzed with AutoDock Vina using PyRX 0.9 software against MFN-2, SwissADME, and GUSAR. Results: Results from screening studies revealed that three compounds (Liriodenine, Pinocembrin, and Vestitol) show an affinity for amino acids present in the predicted active interface of the MFN-2 protein. Moreover, these compounds render low toxicity and efficient ADME qualities, combined with blood-brain barrier permeability, drug-likeness, and lead-likeness. Conclusion: Liriodenine, pinocembrin and vestitol are therapeutic compounds for CMT-2 treatment and should be used in further in-vitro studies to confirm the results of this research.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"34 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136023989","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 : 2023-09-11DOI: 10.2174/1570180820666230911130135
Mohamad Norisham Mohamad Rosdi, Mohamad Hafizi Abu Bakar, Muhammad Helmi Nadri, Husnul Hanani Soib, Nur Hanisah Azmi
background: Fruits like berries are known not only for their taste and nutritional value but also for the potential health benefits of their bioactive components. Stilbenes, a group of phenolic metabolites found in berries, demonstrate significant pharmacological activities. Its derivatives also have been investigated for their biological functions, including as anticancer agents. Bcl-2 antiapoptotic proteins are highly involved in regulating cancer progression by promoting apoptosis evasion. Hence, Bcl-2 is a promising therapeutic target in drug development. objective: This study aimed to determine the stilbene derivatives with the best potential as Bcl-2 inhibitors. method: The method used was molecular docking of several stilbene derivatives to Bcl-2 receptors using AutoDock 4.2, followed by an ADMET study results: Based on the docking score and ligand-receptor interactions, oxyresveratol and pterostilbene had the best docking findings for the Bcl-2 antiapoptotic proteins. Among these eleven substances, pterostilbene significantly inhibited Bcl-w and Mcl-1, whereas oxresveratrol could inhibit Bcl-2. Although the findings from the two ADMET profiles were varied, further in vitro and in vivo studies are required to explore the potential of the compounds. conclusion: In conclusion, the study identified the potential chemopreventive agents, such as pterostilbene and oxyresveratrol might serve as potential lead compounds for developing new Bcl-2 inhibitors.
{"title":"Stilbene-based Derivatives as Potential Inhibitors of Bcl-2 Antiapoptotic Proteins: A Molecular Docking Study and ADMET Prediction","authors":"Mohamad Norisham Mohamad Rosdi, Mohamad Hafizi Abu Bakar, Muhammad Helmi Nadri, Husnul Hanani Soib, Nur Hanisah Azmi","doi":"10.2174/1570180820666230911130135","DOIUrl":"https://doi.org/10.2174/1570180820666230911130135","url":null,"abstract":"background: Fruits like berries are known not only for their taste and nutritional value but also for the potential health benefits of their bioactive components. Stilbenes, a group of phenolic metabolites found in berries, demonstrate significant pharmacological activities. Its derivatives also have been investigated for their biological functions, including as anticancer agents. Bcl-2 antiapoptotic proteins are highly involved in regulating cancer progression by promoting apoptosis evasion. Hence, Bcl-2 is a promising therapeutic target in drug development. objective: This study aimed to determine the stilbene derivatives with the best potential as Bcl-2 inhibitors. method: The method used was molecular docking of several stilbene derivatives to Bcl-2 receptors using AutoDock 4.2, followed by an ADMET study results: Based on the docking score and ligand-receptor interactions, oxyresveratol and pterostilbene had the best docking findings for the Bcl-2 antiapoptotic proteins. Among these eleven substances, pterostilbene significantly inhibited Bcl-w and Mcl-1, whereas oxresveratrol could inhibit Bcl-2. Although the findings from the two ADMET profiles were varied, further in vitro and in vivo studies are required to explore the potential of the compounds. conclusion: In conclusion, the study identified the potential chemopreventive agents, such as pterostilbene and oxyresveratrol might serve as potential lead compounds for developing new Bcl-2 inhibitors.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"87 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135981341","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 : 2023-09-08DOI: 10.2174/1570180820666230908144810
Suman B. Chauhan, Uttam A. More, Malleshappa N. Noolvi
Background: Cancer-associated inflammation can be initiated by mutations and can contribute to malignant tumors through the recruitment and activation of inflammatory cells. Tumor necrosis factor (TNF, also known as TNF-α) released from macrophages and T-lymphocytes was known in the late 1970s as having the capability to suppress neoplasm cell proliferation and induce tumor regression. Moreover, some of the sulfonamide derivatives are used as TNF-α inhibitors and in the treatment of inflammatory diseases. Methods: In sillico studies were conducted for the synthesis of a novel series of 1,3,4-thiadiazole derivatives comprising sulfonamide to act as anticancer agents. The structures of synthesized compounds were characterized by various spectroscopic methods, such as Infrared, 1H Nuclear magnetic resonance, and Mass spectroscopy. Subsequently, synthesized compounds were tested for in vitro cytotoxicity against MCF-7 human cancer cell lines using the MTT assay. Results: The docking study revealed that the newly synthesized molecules showed greater docking scores and similar interaction as reference molecules like Celecoxib and Sulfasalazine. Compounds 6a and 6c had more binding affinity onto the TNF-α dimer (PDB Id: 2az5) binding surface due to the extra stability of complex as a result of an extra (π-π) stacking and hydrogen-bond interaction with chain A amino acid TYR 59, TYR 151, TYR119, LEU120, GLY121 and chain B amino acid TYR 59, SER 60, GLN 61 than Celecoxib. Synthesized compounds were tested for in vitro cytotoxicity against MCF-7 human cancer cell lines using the MTT assay. In preliminary MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), cytotoxicity studies of derivatives (6a and 6c) were found to be most effective with IC50 value of 0.052 and 0.047 μM. Conclusion: The synthesized compounds are potential anticancer agents and can be utilized to create novel anticancer drugs, according to the study.
{"title":"Synthesis and Anticancer Activity of Newly Substituted 1,3,4-Thiadiazole Derivatives: A Novel Class of Anticancer Agents","authors":"Suman B. Chauhan, Uttam A. More, Malleshappa N. Noolvi","doi":"10.2174/1570180820666230908144810","DOIUrl":"https://doi.org/10.2174/1570180820666230908144810","url":null,"abstract":"Background: Cancer-associated inflammation can be initiated by mutations and can contribute to malignant tumors through the recruitment and activation of inflammatory cells. Tumor necrosis factor (TNF, also known as TNF-α) released from macrophages and T-lymphocytes was known in the late 1970s as having the capability to suppress neoplasm cell proliferation and induce tumor regression. Moreover, some of the sulfonamide derivatives are used as TNF-α inhibitors and in the treatment of inflammatory diseases. Methods: In sillico studies were conducted for the synthesis of a novel series of 1,3,4-thiadiazole derivatives comprising sulfonamide to act as anticancer agents. The structures of synthesized compounds were characterized by various spectroscopic methods, such as Infrared, 1H Nuclear magnetic resonance, and Mass spectroscopy. Subsequently, synthesized compounds were tested for in vitro cytotoxicity against MCF-7 human cancer cell lines using the MTT assay. Results: The docking study revealed that the newly synthesized molecules showed greater docking scores and similar interaction as reference molecules like Celecoxib and Sulfasalazine. Compounds 6a and 6c had more binding affinity onto the TNF-α dimer (PDB Id: 2az5) binding surface due to the extra stability of complex as a result of an extra (π-π) stacking and hydrogen-bond interaction with chain A amino acid TYR 59, TYR 151, TYR119, LEU120, GLY121 and chain B amino acid TYR 59, SER 60, GLN 61 than Celecoxib. Synthesized compounds were tested for in vitro cytotoxicity against MCF-7 human cancer cell lines using the MTT assay. In preliminary MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide), cytotoxicity studies of derivatives (6a and 6c) were found to be most effective with IC50 value of 0.052 and 0.047 μM. Conclusion: The synthesized compounds are potential anticancer agents and can be utilized to create novel anticancer drugs, according to the study.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"6 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136362037","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 : 2023-09-07DOI: 10.2174/1570180820666230907115841
Rajat Ghosh, Pratap Chandra Acharya
Background: Safe and effective anticancer drug discovery is still a challenge for medicinal chemists. Spirooxindoles have shown promising pre-clinical results in designing newer cancer therapeutic candidates. In order to find out the effect of electron-withdrawing groups on its effect on colon cancer, a series of pyrrolizidine and N-methyl pyrrolidine spirooxindole derivatives were synthesized and evaluated against human colon cancer cell lines. Methods: A highly efficient one-pot, multi component and stereoselective [3+2] cyclo addition reaction were employed to synthesize a series of pyrrolizidine and N-methyl pyrrolidine spirooxindole derivatives with electron-withdrawing methoxy substitutions. This method involves previously optimized reaction condition developed in our lab to achieve excellent regio- and stereoselectivity. The newly synthesized spirooxindole derivatives were evaluated for their antiproliferative efficacy against human colon cancer cell lines HT29 and HCT116. Results: The synthesized compounds were characterized using FTIR, NMR, and ESI-MS. RP-HPLC determined the purity, and the structure while the assigned stereochemistry were confirmed using X-ray crystallography. Compound 14a produced the best antiproliferative activity with IC50 values of 62.66 and 18.48 µM against HT29 and HCT116 human colon cancer cell lines. Conclusion: The described one-pot, multicomponent, [3+2] cycloaddition reaction proved to be a catalyst-free reaction with high atom economy and single-step reaction. The effectiveness of the compounds was determined through in vitro cell viability assays which revealed their potency against colon cancer. Thus the study can be explored further as a hit-to-lead studies by designing compounds with varied substituents.
{"title":"Stereoselective synthesis and antiproliferative effect of methoxylated spirooxindoles on colon cancer cell lines","authors":"Rajat Ghosh, Pratap Chandra Acharya","doi":"10.2174/1570180820666230907115841","DOIUrl":"https://doi.org/10.2174/1570180820666230907115841","url":null,"abstract":"Background: Safe and effective anticancer drug discovery is still a challenge for medicinal chemists. Spirooxindoles have shown promising pre-clinical results in designing newer cancer therapeutic candidates. In order to find out the effect of electron-withdrawing groups on its effect on colon cancer, a series of pyrrolizidine and N-methyl pyrrolidine spirooxindole derivatives were synthesized and evaluated against human colon cancer cell lines. Methods: A highly efficient one-pot, multi component and stereoselective [3+2] cyclo addition reaction were employed to synthesize a series of pyrrolizidine and N-methyl pyrrolidine spirooxindole derivatives with electron-withdrawing methoxy substitutions. This method involves previously optimized reaction condition developed in our lab to achieve excellent regio- and stereoselectivity. The newly synthesized spirooxindole derivatives were evaluated for their antiproliferative efficacy against human colon cancer cell lines HT29 and HCT116. Results: The synthesized compounds were characterized using FTIR, NMR, and ESI-MS. RP-HPLC determined the purity, and the structure while the assigned stereochemistry were confirmed using X-ray crystallography. Compound 14a produced the best antiproliferative activity with IC50 values of 62.66 and 18.48 µM against HT29 and HCT116 human colon cancer cell lines. Conclusion: The described one-pot, multicomponent, [3+2] cycloaddition reaction proved to be a catalyst-free reaction with high atom economy and single-step reaction. The effectiveness of the compounds was determined through in vitro cell viability assays which revealed their potency against colon cancer. Thus the study can be explored further as a hit-to-lead studies by designing compounds with varied substituents.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"7 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135096567","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 : 2023-09-01DOI: 10.2174/1570180819666220422114450
Muhammad Naveed, Noor ul-Ain, Muhammad Aqib Shabbir
Background: Pandemic of COVID-19 has gathered up the surrounding respiratory diseases such as asthma. The need to combat asthma is an unanswerable question nowadays and about 20-30% of people are getting into the trap of asthma. Objectives: The mechanistic involvement of GPCR receptors in the protuberant signaling pathway such as Neuropeptide S receptor 1 (NPSR1 receptor) acts as a projected entry that needs to be inhibited for the prohibition of asthma. Methods: Exaggerative G-proteins of NPSR1 receptors are exposed as a target through GPCR modeling to point drug targeting. Three Drug-Drug Conjugates (DDCs) are designed through the combination of nine chemical compounds through methylene bridges and selection was done based on docking energy and ADMET profiling. Designation of three Monoclonal Antibody Conjugates (MACs) is expedited using single monoclonal antibodies, linked through EAAAK linkers and the best conjugate was valued based on docking energy, allergenicity, toxicity, and surface accessibility leading towards cloning and expression. Results: The best Drug-Drug Conjugate was Fluoroquinolone and 1-Indanone conjugate which possessed -7.7 Kcal/mol docking energy, lipophilicity 6.41, water solubility 1.19e-09 mg/ml, and pharmacokinetics -8.31 cm/s, indicating it to act as best drug candidate. The best Monoclonal Antibody Conjugate was Ustekinumab and Belimumab conjugate which retained -383.1 Kcal/mol docking energy, computed as non-allergen and nontoxic. Conclusion:: The use of MACs and DDCs may prove an effective treatment for lethal diseases like asthma and the future exertion will support the in vitro synthesis delivered in this study of conjugation against bronchial diseases.
{"title":"Computational Drug Shifting Towards Drug-Drug Conjugates and Monoclonal Antibody Conjugates in the Contradictory Excursion of Asthma","authors":"Muhammad Naveed, Noor ul-Ain, Muhammad Aqib Shabbir","doi":"10.2174/1570180819666220422114450","DOIUrl":"https://doi.org/10.2174/1570180819666220422114450","url":null,"abstract":"Background: Pandemic of COVID-19 has gathered up the surrounding respiratory diseases such as asthma. The need to combat asthma is an unanswerable question nowadays and about 20-30% of people are getting into the trap of asthma. Objectives: The mechanistic involvement of GPCR receptors in the protuberant signaling pathway such as Neuropeptide S receptor 1 (NPSR1 receptor) acts as a projected entry that needs to be inhibited for the prohibition of asthma. Methods: Exaggerative G-proteins of NPSR1 receptors are exposed as a target through GPCR modeling to point drug targeting. Three Drug-Drug Conjugates (DDCs) are designed through the combination of nine chemical compounds through methylene bridges and selection was done based on docking energy and ADMET profiling. Designation of three Monoclonal Antibody Conjugates (MACs) is expedited using single monoclonal antibodies, linked through EAAAK linkers and the best conjugate was valued based on docking energy, allergenicity, toxicity, and surface accessibility leading towards cloning and expression. Results: The best Drug-Drug Conjugate was Fluoroquinolone and 1-Indanone conjugate which possessed -7.7 Kcal/mol docking energy, lipophilicity 6.41, water solubility 1.19e-09 mg/ml, and pharmacokinetics -8.31 cm/s, indicating it to act as best drug candidate. The best Monoclonal Antibody Conjugate was Ustekinumab and Belimumab conjugate which retained -383.1 Kcal/mol docking energy, computed as non-allergen and nontoxic. Conclusion:: The use of MACs and DDCs may prove an effective treatment for lethal diseases like asthma and the future exertion will support the in vitro synthesis delivered in this study of conjugation against bronchial diseases.","PeriodicalId":18059,"journal":{"name":"Letters in Drug Design & Discovery","volume":"111 1","pages":"0"},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135685701","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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