Pub Date : 2023-01-01DOI: 10.2174/1573409919666230123144712
Ajay Mahor, Devesh M Sawant, Amit K Goyal
Background: Amphotericin B is a gold-standard drug, particularly for the treatment of systemic fungal infections. However, its low solubility and permeability limit its application. To improve its bioavailability, AmB may be conjugated with various water-soluble auxiliary groups.
Methods: Custom R group Enumeration was used at the designated sites of Amphotericin B. The designated sites taken into consideration are the carboxyl moiety of the aglycone part and the amine moiety of the glycone part of Amphotericin B for Enumeration purposes. The enumerated molecules were subjected to QikProp properties.
Results: We identified fourteen hits with improved predicted aqueous solubility and cell permeability.
Conclusion: Enumeration might be applicable in improving bioavailability, which could lead to the oral formulation of the Amphotericin B drug.
{"title":"The Custom R Group Enumeration with Various R Group Libraries at Designated Sites on Amphotericin B.","authors":"Ajay Mahor, Devesh M Sawant, Amit K Goyal","doi":"10.2174/1573409919666230123144712","DOIUrl":"https://doi.org/10.2174/1573409919666230123144712","url":null,"abstract":"<p><strong>Background: </strong>Amphotericin B is a gold-standard drug, particularly for the treatment of systemic fungal infections. However, its low solubility and permeability limit its application. To improve its bioavailability, AmB may be conjugated with various water-soluble auxiliary groups.</p><p><strong>Methods: </strong>Custom R group Enumeration was used at the designated sites of Amphotericin B. The designated sites taken into consideration are the carboxyl moiety of the aglycone part and the amine moiety of the glycone part of Amphotericin B for Enumeration purposes. The enumerated molecules were subjected to QikProp properties.</p><p><strong>Results: </strong>We identified fourteen hits with improved predicted aqueous solubility and cell permeability.</p><p><strong>Conclusion: </strong>Enumeration might be applicable in improving bioavailability, which could lead to the oral formulation of the Amphotericin B drug.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9472242","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: Network pharmacology based identification of phytochemicals in the form of cocktails against off-targets can play a significant role in inhibition of SARS_CoV2 viral entry and its propagation. This study includes network pharmacology, virtual screening, docking and molecular dynamics to investigate the distinct antiviral mechanisms of effective phytochemicals against SARS_CoV2.
Methods: SARS_CoV2 human-protein interaction network was explored from the BioGRID database and analysed using Cytoscape. Further analysis was performed to explore biological function, protein-phytochemical/drugs network and up-down regulation of pathological host target proteins. This lead to understand the antiviral mechanism of phytochemicals against SARS_CoV2. The network was explored through g:Profiler, EnrichR, CTD, SwissTarget, STITCH, DrugBank, BindingDB, STRING and SuperPred. Virtual screening of phytochemicals against potential antiviral targets such as M-Pro, NSP1, Receptor binding domain, RNA binding domain, and ACE2 discloses the effective interaction between them. Further, the binding energy calculations through simulation of the docked complex explains the efficiency and stability of the interactions.
Results: The network analysis identified quercetin, genistein, luteolin, eugenol, berberine, isorhamnetin and cinnamaldehyde to be interacting with host proteins ACE2, DPP4, COMT, TUBGCP3, CENPF, BRD2 and HMOX1 which are involved in antiviral mechanisms such as viral entry, viral replication, host immune response, and antioxidant activity. Thus indicating that herbal cocktails can effectively tackle the viral hijacking of the crucial biological functions of human host. Further exploration through Virtual screening, docking and molecular dynamics recognizes the effective interaction of phytochemicals such as punicalagin, scutellarin, and solamargine with their respective potential targets.
Conclusion: This work illustrates probable strategy for identification of phytochemical based cocktails and off-targets which are effective against SARS_CoV 2.
{"title":"Molecular insights on bioactive compounds againstCovid-19: A Network pharmacological and computational study.","authors":"Jayanth Jeevanandam, Esackimuthu Paramasivam, Anbumathi Palanisamy, Srikanth Ragavendran, Saraswathi Nambiappan Thangavel","doi":"10.2174/1573409918666220914092145","DOIUrl":"10.2174/1573409918666220914092145","url":null,"abstract":"<p><strong>Background: </strong>Network pharmacology based identification of phytochemicals in the form of cocktails against off-targets can play a significant role in inhibition of SARS_CoV2 viral entry and its propagation. This study includes network pharmacology, virtual screening, docking and molecular dynamics to investigate the distinct antiviral mechanisms of effective phytochemicals against SARS_CoV2.</p><p><strong>Methods: </strong>SARS_CoV2 human-protein interaction network was explored from the BioGRID database and analysed using Cytoscape. Further analysis was performed to explore biological function, protein-phytochemical/drugs network and up-down regulation of pathological host target proteins. This lead to understand the antiviral mechanism of phytochemicals against SARS_CoV2. The network was explored through g:Profiler, EnrichR, CTD, SwissTarget, STITCH, DrugBank, BindingDB, STRING and SuperPred. Virtual screening of phytochemicals against potential antiviral targets such as M-Pro, NSP1, Receptor binding domain, RNA binding domain, and ACE2 discloses the effective interaction between them. Further, the binding energy calculations through simulation of the docked complex explains the efficiency and stability of the interactions.</p><p><strong>Results: </strong>The network analysis identified quercetin, genistein, luteolin, eugenol, berberine, isorhamnetin and cinnamaldehyde to be interacting with host proteins ACE2, DPP4, COMT, TUBGCP3, CENPF, BRD2 and HMOX1 which are involved in antiviral mechanisms such as viral entry, viral replication, host immune response, and antioxidant activity. Thus indicating that herbal cocktails can effectively tackle the viral hijacking of the crucial biological functions of human host. Further exploration through Virtual screening, docking and molecular dynamics recognizes the effective interaction of phytochemicals such as punicalagin, scutellarin, and solamargine with their respective potential targets.</p><p><strong>Conclusion: </strong>This work illustrates probable strategy for identification of phytochemical based cocktails and off-targets which are effective against SARS_CoV 2.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2022-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40362942","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":null,"pages":null},"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 : 2022-09-01DOI: 10.2174/1573409918666220901120750
Jiting Wu, Liming Pan
Background: At present, there is still little research on the anti-aging effect of Pogostemon cablin Benth (PCB) on human skin. In this paper, the mechanism of anti-aging effect of PCB on human skin was studied by using network pharmacology and molecular docking methods.
Objective: To analyze the pharmacological mechanism of PCB in the treatment of skin aging, so as to provide reference for new drug development and clinical application.
Methods: Active ingredients and related targets of PCB and skin aging-related disease targets are obtained through public databases, and the "drug-disease-target" and protein-protein interaction (PPI) network diagrams were constructed with the help of software to screen the core targets; Then GO analysis and KEGG pathway analysis were performed on the target; Finally, the molecular docking between the components and the targets were verified.
Results: After screening, 112 intersection targets of active compounds of skin aging and PCB were obtained. Through GO and KEGG enrichment analysis, it is found that these biological processes mainly focus on epithelial cell proliferation, aging, growth factors, longevity regulation pathway, cancer pathway, AGE-RAGE signal pathway, PI3K Akt signal pathway and IL-17 signal pathway. The molecular docking results showed that quercetin, apigenin, irisnepalensis isoflavone, 3,23-dihydroxy-12-oleorene-28-oleic acid, 5-hydroxy-7,4'- dimethoxyflavone and other major compounds were connected with TP53, JUN, HSP90AAL, AKT1 and MAPK1 through hydrogen bonds, and there was high binding energy between them.
Conclusion: Through multi-target prediction and molecular docking verification, it shows that PCB provides a strong effect in the treatment of skin aging, which provides a reference for its further research.
{"title":"Study on the effect of Pogostemon cablin Benth on skin aging based on network pharmacology.","authors":"Jiting Wu, Liming Pan","doi":"10.2174/1573409918666220901120750","DOIUrl":"10.2174/1573409918666220901120750","url":null,"abstract":"<p><strong>Background: </strong>At present, there is still little research on the anti-aging effect of Pogostemon cablin Benth (PCB) on human skin. In this paper, the mechanism of anti-aging effect of PCB on human skin was studied by using network pharmacology and molecular docking methods.</p><p><strong>Objective: </strong>To analyze the pharmacological mechanism of PCB in the treatment of skin aging, so as to provide reference for new drug development and clinical application.</p><p><strong>Methods: </strong>Active ingredients and related targets of PCB and skin aging-related disease targets are obtained through public databases, and the \"drug-disease-target\" and protein-protein interaction (PPI) network diagrams were constructed with the help of software to screen the core targets; Then GO analysis and KEGG pathway analysis were performed on the target; Finally, the molecular docking between the components and the targets were verified.</p><p><strong>Results: </strong>After screening, 112 intersection targets of active compounds of skin aging and PCB were obtained. Through GO and KEGG enrichment analysis, it is found that these biological processes mainly focus on epithelial cell proliferation, aging, growth factors, longevity regulation pathway, cancer pathway, AGE-RAGE signal pathway, PI3K Akt signal pathway and IL-17 signal pathway. The molecular docking results showed that quercetin, apigenin, irisnepalensis isoflavone, 3,23-dihydroxy-12-oleorene-28-oleic acid, 5-hydroxy-7,4'- dimethoxyflavone and other major compounds were connected with TP53, JUN, HSP90AAL, AKT1 and MAPK1 through hydrogen bonds, and there was high binding energy between them.</p><p><strong>Conclusion: </strong>Through multi-target prediction and molecular docking verification, it shows that PCB provides a strong effect in the treatment of skin aging, which provides a reference for its further research.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40343801","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 : 2022-08-27DOI: 10.2174/1573409918666220827151546
Amar Y Al-Ansi, Zijing Lin
Aim: Developing a method for use in computer aided drug design Background: Predicting the structure of enzyme-ligand binding mode is essential for understanding the properties, functions, and mechanisms of the bio-complex, but is rather difficult due to the enormous sampling space involved.
Objective: Accurate prediction of enzyme-ligand binding mode conformation.
Method: A new computational protocol, MDO, is proposed for finding the structure of ligand binding pose. MDO consists of sampling enzyme sidechain conformations via molecular dynamics simulation of enzyme-ligand system and clustering of the enzyme configurations, sampling ligand binding poses via molecular docking and clustering of the ligand conformations, and the optimal ligand binding pose prediction via geometry optimization and ranking by the ONIOM method. MDO is tested on 15 enzyme-ligand complexes with known accurate structures.
Results: The success rate of MDO predictions, with RMSD < 2 Å, is 67%, substantially higher than the 40% success rate of conventional methods. The MDO success rate can be increased to 83% if the ONIOM calculations are applied only for the starting poses with ligands inside the binding cavities.
Conclusion: The MDO protocol provides high quality enzyme-ligand binding mode prediction with reasonable computational cost. The MDO protocol is recommended for use in the structure-based drug design.
{"title":"MDO: A Computational Protocol for Prediction of Flexible Enzyme-Ligand Binding Mode.","authors":"Amar Y Al-Ansi, Zijing Lin","doi":"10.2174/1573409918666220827151546","DOIUrl":"10.2174/1573409918666220827151546","url":null,"abstract":"<p><strong>Aim: </strong>Developing a method for use in computer aided drug design Background: Predicting the structure of enzyme-ligand binding mode is essential for understanding the properties, functions, and mechanisms of the bio-complex, but is rather difficult due to the enormous sampling space involved.</p><p><strong>Objective: </strong>Accurate prediction of enzyme-ligand binding mode conformation.</p><p><strong>Method: </strong>A new computational protocol, MDO, is proposed for finding the structure of ligand binding pose. MDO consists of sampling enzyme sidechain conformations via molecular dynamics simulation of enzyme-ligand system and clustering of the enzyme configurations, sampling ligand binding poses via molecular docking and clustering of the ligand conformations, and the optimal ligand binding pose prediction via geometry optimization and ranking by the ONIOM method. MDO is tested on 15 enzyme-ligand complexes with known accurate structures.</p><p><strong>Results: </strong>The success rate of MDO predictions, with RMSD < 2 Å, is 67%, substantially higher than the 40% success rate of conventional methods. The MDO success rate can be increased to 83% if the ONIOM calculations are applied only for the starting poses with ligands inside the binding cavities.</p><p><strong>Conclusion: </strong>The MDO protocol provides high quality enzyme-ligand binding mode prediction with reasonable computational cost. The MDO protocol is recommended for use in the structure-based drug design.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2022-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40331436","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 : 2022-08-20DOI: 10.2174/1573409918666220820160834
Amritha A M, Shakhi Shylesh C M, Kavyanjana R Nair, Arya V S, Thennavan Arumugam, Uma Devi P, Kanthlal Sk
Background: The mechanisms that cause a patient's blood pressure to rise are diverse. Controlling blood pressure with monotherapy acting through a single pathway may be unachievable. Combining a clinically used medication with herbal medicine can result in an antihypertensive effect that is two to five times greater than monotherapy.
Method: This study examined the effects of aqueous extracts of large cardamom and ramipril on the redox biology of nitric oxide and vascular reactivity in the isolated aorta incubated with a nitro-L-arginine methyl ester. Molecular docking study was performed to predict the affinity of constituents of large cardamom extracts with the NOX 2 gene.
Results: Nitric oxide (NO) levels, disordered antioxidant enzymes (glutathione and catalase), NADPH oxidase and lipid peroxidation were recovered when aqueous extract of large cardamom and ramipril were combined. A gradual increase in the percentage relaxation of acetylcholine in phenylephrine pre-contracted aorta indicates that the combination therapy prevents endothelial damage. The molecular docking study reveals the important phytoconstituents present in the large cardamom that can effectively bind with the NADPH oxidase for its antioxidant activity. Consculsion: According to our findings, it was evidenced that the large cardamom extract's vasoprotective action was mostly related to its ability to restore endothelial redox biology by suppressing NADPH oxidase activity. Our findings suggest that ramipril's direct impact on the eNOS/NO system, along with the antioxidant properties of AELC, could have a synergetic benefit in the treatment of hypertension, as well as lessen ramipril's existing side effects.
{"title":"Large Cardamom Extract Enhances Ramipril's Vasoprotective Action in the Aorta by Modulating Endothelial Redox Biology. An Evaluation based on In-silico and In-vitro Research.","authors":"Amritha A M, Shakhi Shylesh C M, Kavyanjana R Nair, Arya V S, Thennavan Arumugam, Uma Devi P, Kanthlal Sk","doi":"10.2174/1573409918666220820160834","DOIUrl":"10.2174/1573409918666220820160834","url":null,"abstract":"<p><strong>Background: </strong>The mechanisms that cause a patient's blood pressure to rise are diverse. Controlling blood pressure with monotherapy acting through a single pathway may be unachievable. Combining a clinically used medication with herbal medicine can result in an antihypertensive effect that is two to five times greater than monotherapy.</p><p><strong>Method: </strong>This study examined the effects of aqueous extracts of large cardamom and ramipril on the redox biology of nitric oxide and vascular reactivity in the isolated aorta incubated with a nitro-L-arginine methyl ester. Molecular docking study was performed to predict the affinity of constituents of large cardamom extracts with the NOX 2 gene.</p><p><strong>Results: </strong>Nitric oxide (NO) levels, disordered antioxidant enzymes (glutathione and catalase), NADPH oxidase and lipid peroxidation were recovered when aqueous extract of large cardamom and ramipril were combined. A gradual increase in the percentage relaxation of acetylcholine in phenylephrine pre-contracted aorta indicates that the combination therapy prevents endothelial damage. The molecular docking study reveals the important phytoconstituents present in the large cardamom that can effectively bind with the NADPH oxidase for its antioxidant activity. Consculsion: According to our findings, it was evidenced that the large cardamom extract's vasoprotective action was mostly related to its ability to restore endothelial redox biology by suppressing NADPH oxidase activity. Our findings suggest that ramipril's direct impact on the eNOS/NO system, along with the antioxidant properties of AELC, could have a synergetic benefit in the treatment of hypertension, as well as lessen ramipril's existing side effects.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2022-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40648596","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 : 2022-08-04DOI: 10.2174/1573409918666220804142753
Ganesh Pavale, Poornima Acharya, Nilesh Korgavkar, M M V Ramana
Background: Quinoxaline and Tetrahydropyridine derivatives showed various biological properties. The combination of these two scaffolds may contribute to good biological activity and may give novel and efficacious bioactive candidates.
Objective: The present study aimed to identify bioactive agents with quinoxaline bearing tetrahydropyridine derivatives possessing anticancer, antioxidant, and anti-tubercular agents.
Method: A series of novel quinoxaline bearing tetrahydropyridine derivatives have been designed and synthesized in good yields. The synthetic protocol involves three-component Povarov reactions of 6-amino quinoxaline, propenyl guaethol, and substituted aldehydes using BF3•OEt2 as catalyst. The newly synthesized molecules were evaluated for their anticancer activity against four cell lines, i.e. A-549, MCF-7, PC-3, and HepG2.
Results: The results from in vitro assay indicated that compound 4a proved to be as potent as the standard drug adriamycin against all cell lines with GI50 values <10 μg/ml. Compounds 4b, 4f, and 4i exhibited good cytotoxicity against A-549 cell line. All synthesized molecules were evaluated for their antioxidant activity and the results revealed that the compounds 4a, 4b, and 4i showed promising antioxidant activities against DPPH and H2O2 scavenging. In addition, the anti-mycobacterial activity of the synthesized compounds against MTB H37Rv strain was determined using MABA method. The results indicate that the compounds 4a, 4b, 4g, and 4i showed better anti-mycobacterial activity than the standard drugs pyrazinamide, ciprofloxacin and streptomycin with MIC value 1.6 μg/ml. Furthermore, molecular docking studies and ADME properties showed good pharmacokinetic profile and drug-likeness properties.
Conclusion: These studies showed that a series of novel quinoxaline bearing tetrahydropyridine derivatives exhibit anticancer, anti-mycobacterial, and antioxidant activities.
{"title":"Design, Synthesis, and Biological Evaluation of quinoxaline bearing tetrahydropyridine derivatives as anticancer, antioxidant, and anti-tubercular agents.","authors":"Ganesh Pavale, Poornima Acharya, Nilesh Korgavkar, M M V Ramana","doi":"10.2174/1573409918666220804142753","DOIUrl":"10.2174/1573409918666220804142753","url":null,"abstract":"<p><strong>Background: </strong>Quinoxaline and Tetrahydropyridine derivatives showed various biological properties. The combination of these two scaffolds may contribute to good biological activity and may give novel and efficacious bioactive candidates.</p><p><strong>Objective: </strong>The present study aimed to identify bioactive agents with quinoxaline bearing tetrahydropyridine derivatives possessing anticancer, antioxidant, and anti-tubercular agents.</p><p><strong>Method: </strong>A series of novel quinoxaline bearing tetrahydropyridine derivatives have been designed and synthesized in good yields. The synthetic protocol involves three-component Povarov reactions of 6-amino quinoxaline, propenyl guaethol, and substituted aldehydes using BF3•OEt2 as catalyst. The newly synthesized molecules were evaluated for their anticancer activity against four cell lines, i.e. A-549, MCF-7, PC-3, and HepG2.</p><p><strong>Results: </strong>The results from in vitro assay indicated that compound 4a proved to be as potent as the standard drug adriamycin against all cell lines with GI50 values <10 μg/ml. Compounds 4b, 4f, and 4i exhibited good cytotoxicity against A-549 cell line. All synthesized molecules were evaluated for their antioxidant activity and the results revealed that the compounds 4a, 4b, and 4i showed promising antioxidant activities against DPPH and H2O2 scavenging. In addition, the anti-mycobacterial activity of the synthesized compounds against MTB H37Rv strain was determined using MABA method. The results indicate that the compounds 4a, 4b, 4g, and 4i showed better anti-mycobacterial activity than the standard drugs pyrazinamide, ciprofloxacin and streptomycin with MIC value 1.6 μg/ml. Furthermore, molecular docking studies and ADME properties showed good pharmacokinetic profile and drug-likeness properties.</p><p><strong>Conclusion: </strong>These studies showed that a series of novel quinoxaline bearing tetrahydropyridine derivatives exhibit anticancer, anti-mycobacterial, and antioxidant activities.</p>","PeriodicalId":10886,"journal":{"name":"Current computer-aided drug design","volume":null,"pages":null},"PeriodicalIF":1.7,"publicationDate":"2022-08-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40585139","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":null,"pages":null},"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":null,"pages":null},"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":null,"pages":null},"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}