Pub Date : 2023-01-01DOI: 10.2174/1573409919666221227091735
Vijay J Desale, Suraj N Mali, Bapu R Thorat, Ramesh S Yamgar, Swapnali V Dharanguttikar, Vyankatesh R Dharanguttikar, Samir Chtita, Mozaniel Oliveira, Jorddy Neves Cruz
Background: Hydrazide-hydrazone derivatives have shown diverse biological activities, such as antitubercular (anti-TB), antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal actions.
Objectives: Hydrazide-hydrazones contain azomethine (-NH-N=CH-) group connected with carbonyl group and are believed to be responsible for various pharmaceutical applications. They aid in the synthesis of different five-membered heterocyclic systems, such as oxadiazole, triazoles, etc. Methods: In the present study, various hydrazines/hydrazones were synthesized starting from 4- amino benzoic acid derivatives. Structures of all 9 newly synthesized compounds (6a-6d and 8a- 8e) were further characterized by using various spectroscopic methods, such as 1H-NMR (Nuclear Magnetic Resonance), FT-IR (Fourier-transform infrared spectroscopy), Gas chromatographymass spectrometry (GC-MS), etc. Furthermore, molecular docking analysis against the acyl-CoA carboxylase, AccD5 (PDB ID: 2A7S), was also carried out using the Glide module, which depicted good binding scores than standard drugs. The anti-tuberculosis activity of all the hydrazides and hydrazones (6a-6d and 8a-8e) were evaluated against the Mycobacterium tuberculosis H37 RV strain using the Alamar-Blue susceptibility (MABA) test. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL values. The antioxidant activity was also carried out using a DPPH assay.
Results: Our findings demonstrated highly encouraging in-vitro results (MABA assay, MIC: 1.2 μg/mL) of hydrazones as depicted by good antimycobacterial activity. The antioxidant results showed a moderate to a good percentage of DPPH inhibition. Our in-silico ADMET analysis further suggested good pharmacokinetic and toxicity-free profiles of synthesized analogues (6a-6d and 8a-8e).
Conclusion: Our results signify hydrazones/hydrazines as potential hit candidates against the future developments of potent and safer anti-TB agents.
{"title":"Synthesis, Characterization, 'ADMET-SAR' Prediction, DPPH Assay, and Anti-Mycobacterium Study of 4-[(substituted benzyl) amino]benzo hydrazides and its Hydrazones as the Acyl-CoA Carboxylase, AccD5 Inhibitors.","authors":"Vijay J Desale, Suraj N Mali, Bapu R Thorat, Ramesh S Yamgar, Swapnali V Dharanguttikar, Vyankatesh R Dharanguttikar, Samir Chtita, Mozaniel Oliveira, Jorddy Neves Cruz","doi":"10.2174/1573409919666221227091735","DOIUrl":"https://doi.org/10.2174/1573409919666221227091735","url":null,"abstract":"<p><strong>Background: </strong>Hydrazide-hydrazone derivatives have shown diverse biological activities, such as antitubercular (anti-TB), antibacterial, antifungal, anticancer, anti-inflammatory, antiviral, and antiprotozoal actions.</p><p><strong>Objectives: </strong>Hydrazide-hydrazones contain azomethine (-NH-N=CH-) group connected with carbonyl group and are believed to be responsible for various pharmaceutical applications. They aid in the synthesis of different five-membered heterocyclic systems, such as oxadiazole, triazoles, etc. Methods: In the present study, various hydrazines/hydrazones were synthesized starting from 4- amino benzoic acid derivatives. Structures of all 9 newly synthesized compounds (6a-6d and 8a- 8e) were further characterized by using various spectroscopic methods, such as <sup>1</sup>H-NMR (Nuclear Magnetic Resonance), FT-IR (Fourier-transform infrared spectroscopy), Gas chromatographymass spectrometry (GC-MS), etc. Furthermore, molecular docking analysis against the acyl-CoA carboxylase, AccD5 (PDB ID: 2A7S), was also carried out using the Glide module, which depicted good binding scores than standard drugs. The anti-tuberculosis activity of all the hydrazides and hydrazones (6a-6d and 8a-8e) were evaluated against the Mycobacterium tuberculosis H37 RV strain using the Alamar-Blue susceptibility (MABA) test. The activity was expressed as the minimum inhibitory concentration (MIC) in μg/mL values. The antioxidant activity was also carried out using a DPPH assay.</p><p><strong>Results: </strong>Our findings demonstrated highly encouraging in-vitro results (MABA assay, MIC: 1.2 μg/mL) of hydrazones as depicted by good antimycobacterial activity. The antioxidant results showed a moderate to a good percentage of DPPH inhibition. Our in-silico ADMET analysis further suggested good pharmacokinetic and toxicity-free profiles of synthesized analogues (<i>6a-6d</i> and <i>8a-8e</i>).</p><p><strong>Conclusion: </strong>Our results signify hydrazones/hydrazines as potential hit candidates against the future developments of potent and safer anti-TB agents.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"19 4","pages":"300-312"},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9553484","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 : 2022-09-09DOI: 10.2174/1573409918666220909094645
Vikas Yadav
The coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a serious global healthcare crisis, so there is an emergence of identifying efficacious therapeutic options. In a setting where there is an unavailability of definitive medication along with the constant eruption of vaccine-related controversies, the drug-repositioning approach seems to be an ideal step for the management of COVID-19 patients. Fluoroquinolones (FQs) are commonly prescribed antibiotics for the treatment of genitourinary tract and upper respiratory tract infections, including severe community-acquired pneumonia. Research over the years has postulated multifaceted implications of FQs in various pathological conditions. Previously, it has been reported that few, but not all FQs, possess strong antiviral activity with an unknown mechanism of action. Herein, an interesting perspective is discussed on repositioning possibilities of FQs for the SARS-CoV-2 infections based on the recent in silico evidential support. Noteworthy, FQs possess immunomodulatory and bactericidal activity which could be valuable for patients dealing with COVID-19 related complications. Conclusively, the current perspective could pave the way to initiate pre-clinical testing of FQs against several strains of SARS-CoV-2.
{"title":"Computational evidence based perspective on the plausible repositioning of fluoroquinolones for COVID-19 treatment.","authors":"Vikas Yadav","doi":"10.2174/1573409918666220909094645","DOIUrl":"10.2174/1573409918666220909094645","url":null,"abstract":"<p><p>The coronavirus disease (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a serious global healthcare crisis, so there is an emergence of identifying efficacious therapeutic options. In a setting where there is an unavailability of definitive medication along with the constant eruption of vaccine-related controversies, the drug-repositioning approach seems to be an ideal step for the management of COVID-19 patients. Fluoroquinolones (FQs) are commonly prescribed antibiotics for the treatment of genitourinary tract and upper respiratory tract infections, including severe community-acquired pneumonia. Research over the years has postulated multifaceted implications of FQs in various pathological conditions. Previously, it has been reported that few, but not all FQs, possess strong antiviral activity with an unknown mechanism of action. Herein, an interesting perspective is discussed on repositioning possibilities of FQs for the SARS-CoV-2 infections based on the recent in silico evidential support. Noteworthy, FQs possess immunomodulatory and bactericidal activity which could be valuable for patients dealing with COVID-19 related complications. Conclusively, the current perspective could pave the way to initiate pre-clinical testing of FQs against several strains of SARS-CoV-2.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":" ","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"33468166","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 : 2022-06-16DOI: 10.2174/1573409918666220616121449
Mebarka Imane Benguechoua, K. Benarous, Ziyad Benahmed, Sarah Boukhalkhal, Artur M. S. Silva, M. Yousfi
BACKGROUND Through this study, the Chemical composition realized by UHPLC-DAD-ESI-MSn allowed the detection of different phenolic compounds groups from Pistacia atlantica Desf. leaves extracts. We studied the inhibition of main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 by the identified molecules through molecular docking. OBJECTIVE The objective of this study is to identify compounds from Pistacia atlantica Desf. leaves extracts, which might have anti-viral effects. METHODS Chemical composition realized by UHPLC-DAD-ESI-MSn, the inhibition of main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 is studied using molecular docking with Autodock Vina software. ADMET analysis was carried out. RESULTS The identified compounds are quinic acid, digallic acid, galloylquinic acid, gallic acid, trigallic acid, digalloylquinic acids, trigalloylquinic acids and methyl gallate; digallic and quinic acids are the best inhibitors. Digallic acid had binding affinity energy (BAE) of -8.2 kcal/mol, and Ki of 1µM for the CL3 Mpro, Ki of 0.62 mM for the RdRp. Quinic acid showed Ki of 4.6 mM, recorded for both enzymes. Through ADMET analysis, we have found that the two molecules are good drugs candidate. CONCLUSION This is the first time that a group of identified compounds from Pistacia atlantica Desf. leaves is studied for their potential activity against the novel virus by inhibiting two key enzymes in its life cycle, and no further studies have been published in this context.
{"title":"Quinic and digallic acids from Pistacia atlantica Desf. leaves extracts as potent dual effect inhibitors against main protease and RNA-dependent RNA polymerase of SARS-CoV-2.","authors":"Mebarka Imane Benguechoua, K. Benarous, Ziyad Benahmed, Sarah Boukhalkhal, Artur M. S. Silva, M. Yousfi","doi":"10.2174/1573409918666220616121449","DOIUrl":"https://doi.org/10.2174/1573409918666220616121449","url":null,"abstract":"BACKGROUND\u0000Through this study, the Chemical composition realized by UHPLC-DAD-ESI-MSn allowed the detection of different phenolic compounds groups from Pistacia atlantica Desf. leaves extracts. We studied the inhibition of main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 by the identified molecules through molecular docking.\u0000\u0000\u0000OBJECTIVE\u0000The objective of this study is to identify compounds from Pistacia atlantica Desf. leaves extracts, which might have anti-viral effects.\u0000\u0000\u0000METHODS\u0000Chemical composition realized by UHPLC-DAD-ESI-MSn, the inhibition of main protease (CL3 Mpro) and RNA-dependent RNA polymerase (RdRp) of the SARS-CoV-2 is studied using molecular docking with Autodock Vina software. ADMET analysis was carried out.\u0000\u0000\u0000RESULTS\u0000The identified compounds are quinic acid, digallic acid, galloylquinic acid, gallic acid, trigallic acid, digalloylquinic acids, trigalloylquinic acids and methyl gallate; digallic and quinic acids are the best inhibitors. Digallic acid had binding affinity energy (BAE) of -8.2 kcal/mol, and Ki of 1µM for the CL3 Mpro, Ki of 0.62 mM for the RdRp. Quinic acid showed Ki of 4.6 mM, recorded for both enzymes. Through ADMET analysis, we have found that the two molecules are good drugs candidate.\u0000\u0000\u0000CONCLUSION\u0000This is the first time that a group of identified compounds from Pistacia atlantica Desf. leaves is studied for their potential activity against the novel virus by inhibiting two key enzymes in its life cycle, and no further studies have been published in this context.","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"7 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-06-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74740059","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}
BACKGROUND Circular RNAs (circRNAs) act as competing endogenous RNAs (ceRNAs) that indirectly regulate gene expression and function by binding microRNAs (miRNAs). A growing body of evidence indicates that the ceRNA networks can be used as an effective method to investigate cancer; however, the construction and analysis of ceRNA networks, especially circRNA-miRNA-mRNA regulatory network, in different subtypes of breast cancer has not been previously performed. OBJECTIVES In the present study, we generated a ceRNA network to explore their roles in two BC subtypes, namely Luminal A and triple negative breast cancer (TNBC). METHODS First, the expression profiles of circRNA, miRNA, and mRNA were downloaded from the GEO database, differentially expressed genes were obtained using GEO2R, and a ceRNA network, was constructed based on circRNA-miRNA pairs and miRNA-mRNA pairs, which was consisted of 10 circRNAs, 25 miRNAs and 39 mRNAs. Further studies of BC subtypes based on TCGA datasets were also performed to validate the effect of novel ceRNA network. RESULTS AND DISCUSSION Then, the related genes in the regulatory network were analyzed by GO functional annotation and KEGG pathway enrichment. The analysis showed that targeted genes were enriched in 97 GO terms and 25 KEGG pathways, respectively, involved in the molecular typing of breast cancer. Meanwhile, Kaplan-Meier analysis revealed that three key genes (MKI67, DEF8, and GFRA1) were significantly associated with BC tumor differentiation and prognosis. CONCLUSION The current study provides a potential application of ceRNA network within BC subtypes, and may offer new targets for their diagnosis, therapy and prognosis.
{"title":"Construction and investigation of circRNA-associated ceRNA regulatory network in molecular subtypes of breast cancer.","authors":"Yinming Zhong, Sicen Pan, Shunji Zhi, Yue Li, Zhiping Xiu, Changran Wei, Jiesi Luo","doi":"10.2174/1573409918666220615151614","DOIUrl":"https://doi.org/10.2174/1573409918666220615151614","url":null,"abstract":"BACKGROUND\u0000Circular RNAs (circRNAs) act as competing endogenous RNAs (ceRNAs) that indirectly regulate gene expression and function by binding microRNAs (miRNAs). A growing body of evidence indicates that the ceRNA networks can be used as an effective method to investigate cancer; however, the construction and analysis of ceRNA networks, especially circRNA-miRNA-mRNA regulatory network, in different subtypes of breast cancer has not been previously performed.\u0000\u0000\u0000OBJECTIVES\u0000In the present study, we generated a ceRNA network to explore their roles in two BC subtypes, namely Luminal A and triple negative breast cancer (TNBC).\u0000\u0000\u0000METHODS\u0000First, the expression profiles of circRNA, miRNA, and mRNA were downloaded from the GEO database, differentially expressed genes were obtained using GEO2R, and a ceRNA network, was constructed based on circRNA-miRNA pairs and miRNA-mRNA pairs, which was consisted of 10 circRNAs, 25 miRNAs and 39 mRNAs. Further studies of BC subtypes based on TCGA datasets were also performed to validate the effect of novel ceRNA network.\u0000\u0000\u0000RESULTS AND DISCUSSION\u0000Then, the related genes in the regulatory network were analyzed by GO functional annotation and KEGG pathway enrichment. The analysis showed that targeted genes were enriched in 97 GO terms and 25 KEGG pathways, respectively, involved in the molecular typing of breast cancer. Meanwhile, Kaplan-Meier analysis revealed that three key genes (MKI67, DEF8, and GFRA1) were significantly associated with BC tumor differentiation and prognosis.\u0000\u0000\u0000CONCLUSION\u0000The current study provides a potential application of ceRNA network within BC subtypes, and may offer new targets for their diagnosis, therapy and prognosis.","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"11 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80124419","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 : 2022-06-10DOI: 10.2174/1573409918666220610162158
Bapu R Thorat, Suraj N. Mali, Rahul R Wagh, Ramesh S Yamgar
BACKGROUND Hydrazide-hydrazone based compounds are reported for their wider pharmacological potentials. METHODS In present work, we synthesized 10 new Schiff based-aryl-carbohydrazide (3a-3e) and (4a-4e), analogues and characterized further using standard spectroscopic techniques including NMR, mass and FT-IR. Moreover, all synthesized compounds were subjected for in-vitro anti-TB, anti-microbial, antioxidant and anti-MCF-7 cell line studies. RESULTS Our results suggested that compounds are having strong potencies against studied microbial species (such as 3a, 3b and 3c, (anti-TB activity: MIC value of 1.6 µg/mL; 3c:80.23 % inhibition at 200 µg/mL against MCF-7). Synthesized compounds (3a-3e) and (4a-4e) were also retained with higher docking scores than standards like ciprofloxacin; when studied for their molecular docking analysis against common anti-bacterial (pdb id:1d7u; 3a: -4.909 kcal/mol), common anti-fungal (pdb id:1ai9; 3b: -6.122 kcal/mol) and enoyl acyl reductase enzyme (pdb id:2x22; 3c: docking score: -4.194 kcal/mol)) targets. CONCLUSION Thus, considering promising results for Schiff based-aryl-carbohydrazides, these compounds may emerge as new class for the development of potent anti-microbial agents in near future.
{"title":"Synthesis, Molecular docking, Antioxidant, Anti-TB, and potent MCF-7 anticancerstudies of Novel Aryl-carbohydrazideanalogues.","authors":"Bapu R Thorat, Suraj N. Mali, Rahul R Wagh, Ramesh S Yamgar","doi":"10.2174/1573409918666220610162158","DOIUrl":"https://doi.org/10.2174/1573409918666220610162158","url":null,"abstract":"BACKGROUND\u0000Hydrazide-hydrazone based compounds are reported for their wider pharmacological potentials.\u0000\u0000\u0000METHODS\u0000In present work, we synthesized 10 new Schiff based-aryl-carbohydrazide (3a-3e) and (4a-4e), analogues and characterized further using standard spectroscopic techniques including NMR, mass and FT-IR. Moreover, all synthesized compounds were subjected for in-vitro anti-TB, anti-microbial, antioxidant and anti-MCF-7 cell line studies.\u0000\u0000\u0000RESULTS\u0000Our results suggested that compounds are having strong potencies against studied microbial species (such as 3a, 3b and 3c, (anti-TB activity: MIC value of 1.6 µg/mL; 3c:80.23 % inhibition at 200 µg/mL against MCF-7). Synthesized compounds (3a-3e) and (4a-4e) were also retained with higher docking scores than standards like ciprofloxacin; when studied for their molecular docking analysis against common anti-bacterial (pdb id:1d7u; 3a: -4.909 kcal/mol), common anti-fungal (pdb id:1ai9; 3b: -6.122 kcal/mol) and enoyl acyl reductase enzyme (pdb id:2x22; 3c: docking score: -4.194 kcal/mol)) targets.\u0000\u0000\u0000CONCLUSION\u0000Thus, considering promising results for Schiff based-aryl-carbohydrazides, these compounds may emerge as new class for the development of potent anti-microbial agents in near future.","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"74 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80485810","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 : 2022-05-19DOI: 10.2174/1573409918666220519112027
V. L. Maruthanila, Elancheran Ramakrishnan, S. Mirunalini
BACKGROUND Breast cancer is one of the greatest global dilemmas and the current treatment option is using partial agonists/antagonists to target hormone receptors. Estrogen and aromatase enzymes play important roles in breast cancer. The excessive activity or low-level production of estrogen causes various hormonal problems, particularly breast cancer. Potent breast cancer drugs are Tamoxifen, Paclitaxel, Cyclophosphamide, Trastuzumab, etc., and aromatase inhibitors such as Anastrozole, Letrozole and Exemestane, etc. Generally, Breast cancer drugs initiate a few serious side effects in humans. OBJECTIVES This study has attempted to identify alternative drug candidates from Carica papaya with fewer side effects for the treatment of breast cancer. METHODS To achieve this, we have utilized the computational methods for predicting the properties of bioactive compounds from Carica papaya and determining the target binding affinities using the Schrödinger suite (Maestro 9.5). The ligands and target protein were obtained from the well-known database. There are 35 bioactive compounds identified from Carica papaya, were drawn using ChemDraw software and performed Ligand preparation wizard. QikProp is used for Absorption, Distribution, Metabolism, and Excretion (ADME) analysis. RESULTS From the docking studies, the phytocompounds such as Chlorogenic acid, Myricetin, Quercetin, Isorhamnetin, Catechin showed the highest Glide scores. Among the five bioactive phytocompounds, Chlorogenic acid shows a more interesting Gscore with good binding energy compared with the standards Tamoxifen, Anastrozole, and Letrozole. ADME profiling of the phytocompounds was investigated to find the pharmacokinetic characteristics and drug-likeness Conclusion: Carica papaya derived phytocompounds act as an antiestrogen or aromatase inhibitor to regulate the levels of estrogen and the implications for postmenopausal women and reduce the risk of breast cancer. Therefore, we propose these top five bioactive phytocompound for further investigation through in vitro and in vivo studies.
背景:乳腺癌是全球最大的难题之一，目前的治疗选择是使用部分激动剂/拮抗剂靶向激素受体。雌激素和芳香化酶在乳腺癌中起重要作用。雌激素的过度活动或低水平产生会导致各种激素问题，尤其是乳腺癌。有效的乳腺癌药物有他莫昔芬、紫杉醇、环磷酰胺、曲妥珠单抗等，芳香酶抑制剂如阿那曲唑、来曲唑、依西美坦等。一般来说，乳腺癌药物会对人体产生一些严重的副作用。目的:本研究旨在从番木瓜中寻找副作用较小的乳腺癌治疗替代药物。方法利用计算方法对番木瓜中生物活性化合物的性质进行预测，并利用Schrödinger suite (Maestro 9.5)软件确定其与靶点的结合亲和力。配体和靶蛋白均从知名数据库中获得。从番木瓜中鉴定出35种生物活性化合物，利用ChemDraw软件绘制并进行配体制备向导。QikProp用于吸收、分布、代谢和排泄(ADME)分析。结果在对接研究中，绿原酸、杨梅素、槲皮素、异鼠李素、儿茶素等植物化合物的Glide评分最高。在5种植物活性化合物中，绿原酸与标准化合物他莫昔芬、阿那曲唑和来曲唑相比，具有较好的结合能，Gscore更有趣。结论:番木瓜植物化合物具有抗雌激素或芳香酶抑制剂的作用，可调节雌激素水平，对绝经后妇女具有降低乳腺癌风险的作用。因此，我们推荐这5种生物活性最高的植物化合物，通过体外和体内研究进行进一步的研究。
{"title":"In silico approach and molecular docking studies of potent bioactive compounds of Carica papaya as anti-breast cancer agents.","authors":"V. L. Maruthanila, Elancheran Ramakrishnan, S. Mirunalini","doi":"10.2174/1573409918666220519112027","DOIUrl":"https://doi.org/10.2174/1573409918666220519112027","url":null,"abstract":"BACKGROUND\u0000Breast cancer is one of the greatest global dilemmas and the current treatment option is using partial agonists/antagonists to target hormone receptors. Estrogen and aromatase enzymes play important roles in breast cancer. The excessive activity or low-level production of estrogen causes various hormonal problems, particularly breast cancer. Potent breast cancer drugs are Tamoxifen, Paclitaxel, Cyclophosphamide, Trastuzumab, etc., and aromatase inhibitors such as Anastrozole, Letrozole and Exemestane, etc. Generally, Breast cancer drugs initiate a few serious side effects in humans.\u0000\u0000\u0000OBJECTIVES\u0000This study has attempted to identify alternative drug candidates from Carica papaya with fewer side effects for the treatment of breast cancer.\u0000\u0000\u0000METHODS\u0000To achieve this, we have utilized the computational methods for predicting the properties of bioactive compounds from Carica papaya and determining the target binding affinities using the Schrödinger suite (Maestro 9.5). The ligands and target protein were obtained from the well-known database. There are 35 bioactive compounds identified from Carica papaya, were drawn using ChemDraw software and performed Ligand preparation wizard. QikProp is used for Absorption, Distribution, Metabolism, and Excretion (ADME) analysis.\u0000\u0000\u0000RESULTS\u0000From the docking studies, the phytocompounds such as Chlorogenic acid, Myricetin, Quercetin, Isorhamnetin, Catechin showed the highest Glide scores. Among the five bioactive phytocompounds, Chlorogenic acid shows a more interesting Gscore with good binding energy compared with the standards Tamoxifen, Anastrozole, and Letrozole. ADME profiling of the phytocompounds was investigated to find the pharmacokinetic characteristics and drug-likeness Conclusion: Carica papaya derived phytocompounds act as an antiestrogen or aromatase inhibitor to regulate the levels of estrogen and the implications for postmenopausal women and reduce the risk of breast cancer. Therefore, we propose these top five bioactive phytocompound for further investigation through in vitro and in vivo studies.","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"54 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-05-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80910221","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 : 2022-05-16DOI: 10.2174/1573409918666220516144300
Ke Han Tan, Sek Peng Chin, C. Heh
BACKGROUND The vast diversity of peptide sequences may hinder the effectiveness of screening for potential peptide therapeutics as if searching a needle in a haystack. This study aims to develop a new self-evolving peptide algorithm (SEPA), for easy virtual screening of small linear peptides (three to six amino acids) as potential therapeutic agents with the collaborative use of freely available software can be run on any operating system equipped with a Bash scripting terminal. Mitogen-Inducible Gene 6 (Mig6) protein, a cytoplasmic protein responsible for inhibition and regulation of epidermal growth factor receptor tyrosine kinase was used to demonstrate the algorithm. OBJECTIVE To propose a new method to discover potential novel peptide inhibitor via an automated peptide generation, docking and post-docking analysis algorithm that ranks short peptides by using essential hydrogen bond interaction between peptides and the target receptor. METHOD A library of dockable dipeptides were first created using PyMOL, Open Babel and AutoDockTools, and docked into the target receptor using AutoDock Vina, automatically via a Bash script. The docked peptides were then ranked by hydrogen bond interaction-based thorough interaction analysis, where the top ranked peptides were then elongated, docked, and ranked again. The process repeats until the user-defined peptide length is achieved. RESULTS In the tested example, SEPA bash script was able to identify the tripeptide YYH ranked within top 20 based on the essential hydrogen bond interaction towards the essential amino acid residue ASP837 in the EGFR-TK receptor. CONCLUSIONS SEPA could be an alternative approach for the virtual screening of peptide sequences against drug targets.
肽序列的巨大多样性可能会阻碍筛选潜在肽治疗方法的有效性，就像大海捞针一样。本研究旨在开发一种新的自进化肽算法(SEPA)，用于轻松地虚拟筛选小线性肽(3 - 6个氨基酸)作为潜在的治疗剂，协同使用免费提供的软件可以在任何配备Bash脚本终端的操作系统上运行。有丝分裂原诱导基因6 (mi6)蛋白是一种负责抑制和调节表皮生长因子受体酪氨酸激酶的细胞质蛋白。目的提出一种利用肽段与靶受体之间必需的氢键相互作用对短肽进行排序的自动肽段生成、对接和后对接分析算法来发现潜在的新型肽抑制剂的新方法。方法首先使用PyMOL, Open Babel和AutoDockTools创建可停靠的二肽库，并使用AutoDock Vina通过Bash脚本自动停靠到目标受体。然后通过基于氢键相互作用的全面相互作用分析对对接肽进行排序，其中排名靠前的肽被拉长，对接，并再次排序。该过程重复，直到达到用户定义的肽长度。结果SEPA bash脚本能够根据EGFR-TK受体中必需氨基酸残基ASP837的必需氢键相互作用，识别出排在前20位的三肽YYH。结论ssepa可作为一种虚拟筛选药物靶点肽序列的方法。
{"title":"Automated In silico EGFR Peptide Inhibitor Elongation Using Self-Evolving Peptide Algorithm.","authors":"Ke Han Tan, Sek Peng Chin, C. Heh","doi":"10.2174/1573409918666220516144300","DOIUrl":"https://doi.org/10.2174/1573409918666220516144300","url":null,"abstract":"BACKGROUND\u0000The vast diversity of peptide sequences may hinder the effectiveness of screening for potential peptide therapeutics as if searching a needle in a haystack. This study aims to develop a new self-evolving peptide algorithm (SEPA), for easy virtual screening of small linear peptides (three to six amino acids) as potential therapeutic agents with the collaborative use of freely available software can be run on any operating system equipped with a Bash scripting terminal. Mitogen-Inducible Gene 6 (Mig6) protein, a cytoplasmic protein responsible for inhibition and regulation of epidermal growth factor receptor tyrosine kinase was used to demonstrate the algorithm.\u0000\u0000\u0000OBJECTIVE\u0000To propose a new method to discover potential novel peptide inhibitor via an automated peptide generation, docking and post-docking analysis algorithm that ranks short peptides by using essential hydrogen bond interaction between peptides and the target receptor.\u0000\u0000\u0000METHOD\u0000A library of dockable dipeptides were first created using PyMOL, Open Babel and AutoDockTools, and docked into the target receptor using AutoDock Vina, automatically via a Bash script. The docked peptides were then ranked by hydrogen bond interaction-based thorough interaction analysis, where the top ranked peptides were then elongated, docked, and ranked again. The process repeats until the user-defined peptide length is achieved.\u0000\u0000\u0000RESULTS\u0000In the tested example, SEPA bash script was able to identify the tripeptide YYH ranked within top 20 based on the essential hydrogen bond interaction towards the essential amino acid residue ASP837 in the EGFR-TK receptor.\u0000\u0000\u0000CONCLUSIONS\u0000SEPA could be an alternative approach for the virtual screening of peptide sequences against drug targets.","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"53 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-05-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85892674","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 : 2022-05-11DOI: 10.2174/1573409918666220512000247
Sepideh Taghizad, Khadijeh Behbahaninia, M. Jahromy, A. Davood
BACKGROUND AND OBJECTIVE Phthalimide as the rigid form of ameltolide exhibits a phenytoin-like profile of drug-receptor interaction and is active in the MES model and inactive in the PTZ model as anti-epileptic agent. In this research, based on the isosteric replacement, we have reported the design, preparation, and antiepileptic activity of 13 new analogs of pyrrolopyridine and isoindole. METHODS The designed compounds were prepared by condensing 3, 4-pyridine dicarboxylic anhydride or 4-fluorophthalic anhydride with different respective aryl amines. MES and PTZ induced seizure models were done to evaluate the antiepileptic effect of the prepared ligands. RESULTS The prepared ligands have significantly affect both tonic and clonic seizures. In tonic seizures, the prepared compounds decrease mortality to a significant extent and in clonic seizures showed better frequency and latency significantly. Compounds 9, 12 and 13 were the most potent ligands that were more potent than phenytoin. CONCLUSION It is concluded that the best distance between two aryl parts is two bonds and the substitution of the nitro group at the meta position of the phenyl ring is better than para position. Our research group has been investigating this concept for designing newer compounds with better anticonvulsant activity.
{"title":"Pyrrolopyridine and Isoindole as potential anticonvulsant agents: Design, synthesis and pharmacological evaluation.","authors":"Sepideh Taghizad, Khadijeh Behbahaninia, M. Jahromy, A. Davood","doi":"10.2174/1573409918666220512000247","DOIUrl":"https://doi.org/10.2174/1573409918666220512000247","url":null,"abstract":"BACKGROUND AND OBJECTIVE\u0000Phthalimide as the rigid form of ameltolide exhibits a phenytoin-like profile of drug-receptor interaction and is active in the MES model and inactive in the PTZ model as anti-epileptic agent. In this research, based on the isosteric replacement, we have reported the design, preparation, and antiepileptic activity of 13 new analogs of pyrrolopyridine and isoindole.\u0000\u0000\u0000METHODS\u0000The designed compounds were prepared by condensing 3, 4-pyridine dicarboxylic anhydride or 4-fluorophthalic anhydride with different respective aryl amines. MES and PTZ induced seizure models were done to evaluate the antiepileptic effect of the prepared ligands.\u0000\u0000\u0000RESULTS\u0000The prepared ligands have significantly affect both tonic and clonic seizures. In tonic seizures, the prepared compounds decrease mortality to a significant extent and in clonic seizures showed better frequency and latency significantly. Compounds 9, 12 and 13 were the most potent ligands that were more potent than phenytoin.\u0000\u0000\u0000CONCLUSION\u0000It is concluded that the best distance between two aryl parts is two bonds and the substitution of the nitro group at the meta position of the phenyl ring is better than para position. Our research group has been investigating this concept for designing newer compounds with better anticonvulsant activity.","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"28 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-05-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"85218860","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 : 2022-05-09DOI: 10.2174/1573409918666220509214449
W. C. Tan, S. Othman, S. Lim, Nurshamimi Nor Rashida, Choon Han Heh
BACKGROUND Human papillomavirus (HPV) is a small, non-enveloped double-stranded circular DNA virus. The high-risk types of HPV are claimed to be responsible for over 99% of cervical cancers. One of the essential HPV oncoproteins, E7, is responsible for the escape from G1/S cell cycle arrest in HPV infected cells by binding to the retinoblastoma protein (pRb) through its LXCXE binding site. OBJECTIVES To design a peptide inhibitor targeting HPV E7 through an in silico approach. METHODS In this study, the LXCXE binding domain of pRb is used as a target to design peptide inhibitors using a reverse structure-based approach. The designed amino acid sequence from the B pocket of pRb, named peptide Y, was then further investigated in the in vitro analysis. The cytotoxicity of the peptide was analysed in two cell lines, namely, CaSki, containing an integrated HPV16 genome and HaCaT, an immortalized keratinocyte cell. Cell cycle analysis was also carried out in both cell lines treated with peptide. RESULTS Through in silico approach, a 9-amino acids peptide sequence which formed 4 conventional hydrogen bonds with LXCXE motif was selected for in vitro assay. Based on the cytotoxicity analysis, the peptide showed low toxicity in both cell lines where the cell viability remained over 74% when treated with peptide Y. The peptide also caused an accumulation of cells in G0/G1 (+5.4%) and S phase (+10.2%), and reduction of cells in G2/M phase (-14.9%) in the CaSki cells with no significant effect on normal cells, indicating it is a potential HPV inhibitor. CONCLUSION A peptide inhibitor, peptide Y, that was designed from the LXCXE binding motif in pRb is able to inhibit HPV E7 by causing a cell accumulation effect in G0/G1 and S phases of cell cycle in the HPV transformed cell lines. These findings could contribute as a lead of HPV E7 peptide inhibitor in the future.
{"title":"A Reverse Structure-Based Design of HPV E7 Inhibitor.","authors":"W. C. Tan, S. Othman, S. Lim, Nurshamimi Nor Rashida, Choon Han Heh","doi":"10.2174/1573409918666220509214449","DOIUrl":"https://doi.org/10.2174/1573409918666220509214449","url":null,"abstract":"BACKGROUND\u0000Human papillomavirus (HPV) is a small, non-enveloped double-stranded circular DNA virus. The high-risk types of HPV are claimed to be responsible for over 99% of cervical cancers. One of the essential HPV oncoproteins, E7, is responsible for the escape from G1/S cell cycle arrest in HPV infected cells by binding to the retinoblastoma protein (pRb) through its LXCXE binding site.\u0000\u0000\u0000OBJECTIVES\u0000To design a peptide inhibitor targeting HPV E7 through an in silico approach.\u0000\u0000\u0000METHODS\u0000In this study, the LXCXE binding domain of pRb is used as a target to design peptide inhibitors using a reverse structure-based approach. The designed amino acid sequence from the B pocket of pRb, named peptide Y, was then further investigated in the in vitro analysis. The cytotoxicity of the peptide was analysed in two cell lines, namely, CaSki, containing an integrated HPV16 genome and HaCaT, an immortalized keratinocyte cell. Cell cycle analysis was also carried out in both cell lines treated with peptide.\u0000\u0000\u0000RESULTS\u0000Through in silico approach, a 9-amino acids peptide sequence which formed 4 conventional hydrogen bonds with LXCXE motif was selected for in vitro assay. Based on the cytotoxicity analysis, the peptide showed low toxicity in both cell lines where the cell viability remained over 74% when treated with peptide Y. The peptide also caused an accumulation of cells in G0/G1 (+5.4%) and S phase (+10.2%), and reduction of cells in G2/M phase (-14.9%) in the CaSki cells with no significant effect on normal cells, indicating it is a potential HPV inhibitor.\u0000\u0000\u0000CONCLUSION\u0000A peptide inhibitor, peptide Y, that was designed from the LXCXE binding motif in pRb is able to inhibit HPV E7 by causing a cell accumulation effect in G0/G1 and S phases of cell cycle in the HPV transformed cell lines. These findings could contribute as a lead of HPV E7 peptide inhibitor in the future.","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"39 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78299474","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 : 2022-05-09DOI: 10.2174/1573409918666220509213313
Fatma Kubra Ata, F. Ercan, Serap Yalçın Azarkan
BACKGROUND Annona muricata is a member of the Annonaceae family. This plant has a high concentration of Acetogenin, which gives it excellent therapeutic powers. Researchers have tested this miraculous herb in the treatment of breast cancer cells and observed that it can be a source of anticancer. OBJECTIVE The proposed study focused on screening potent the anticancer biological activity of Annona muricata plant by the in-vitro, in-vivo, and in-silico method. METHODS In-vitro analysis, the IC50 was determined on two-dimensional and three-dimensional breast cancer cells. 2D cells were grown on flat dishes typically made of plastic, while 3D cells were grown using the hanging drop method. İn-vivo analysis, Drosophila melanogaster was preferred and the LC50 was determined. In-silico analysis, molecular docking studies have been carried out on the different classes of Annona muricata Acetogenins against the target proteins. Nearly five Acetogenins were selected from the literature and docking was performed against human Bcl-2, Bad and Akt-1 proteins. RESULTS In-vitro and in-vivo results revealed the IC50 value of 2D MDA-MB-231 cells was 330 μg.mℓ-1, 2D MCF-7 cells were 290 μg.mℓ-1, 3D MCF-7 and MDA-MB-231 cells were about 0.005 g.mℓ-1, and LC50 of Drosophila melanogaster was determined as 0.1 g.mℓ-1. In-silico results revealed the docked complex formed by Isoquercetin showed better binding affinity towards target proteins. CONCLUSION As a result of the analysis, the Annona muricata plant has been observed to be effective against cancer and likely to be a potential drug.
{"title":"In vivo, In vitro and Molecular Modelling Analysis of Isoquercetin, Roseoside, Coreximine, Anonaine, and Arianacin Molecules.","authors":"Fatma Kubra Ata, F. Ercan, Serap Yalçın Azarkan","doi":"10.2174/1573409918666220509213313","DOIUrl":"https://doi.org/10.2174/1573409918666220509213313","url":null,"abstract":"BACKGROUND\u0000Annona muricata is a member of the Annonaceae family. This plant has a high concentration of Acetogenin, which gives it excellent therapeutic powers. Researchers have tested this miraculous herb in the treatment of breast cancer cells and observed that it can be a source of anticancer.\u0000\u0000\u0000OBJECTIVE\u0000The proposed study focused on screening potent the anticancer biological activity of Annona muricata plant by the in-vitro, in-vivo, and in-silico method.\u0000\u0000\u0000METHODS\u0000In-vitro analysis, the IC50 was determined on two-dimensional and three-dimensional breast cancer cells. 2D cells were grown on flat dishes typically made of plastic, while 3D cells were grown using the hanging drop method. İn-vivo analysis, Drosophila melanogaster was preferred and the LC50 was determined. In-silico analysis, molecular docking studies have been carried out on the different classes of Annona muricata Acetogenins against the target proteins. Nearly five Acetogenins were selected from the literature and docking was performed against human Bcl-2, Bad and Akt-1 proteins.\u0000\u0000\u0000RESULTS\u0000In-vitro and in-vivo results revealed the IC50 value of 2D MDA-MB-231 cells was 330 μg.mℓ-1, 2D MCF-7 cells were 290 μg.mℓ-1, 3D MCF-7 and MDA-MB-231 cells were about 0.005 g.mℓ-1, and LC50 of Drosophila melanogaster was determined as 0.1 g.mℓ-1. In-silico results revealed the docked complex formed by Isoquercetin showed better binding affinity towards target proteins.\u0000\u0000\u0000CONCLUSION\u0000As a result of the analysis, the Annona muricata plant has been observed to be effective against cancer and likely to be a potential drug.","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":"1 1","pages":""},"PeriodicalIF":1.7,"publicationDate":"2022-05-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83411760","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}
扫码关注我们
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号