scholarly journals Microsecond molecular dynamics simulations revealed the inhibitory potency of amiloride analogs against SARS-CoV-2 E viroporin

2021 ◽  
Vol 19 (4) ◽  
pp. e48
Author(s):  
Abdullah All Jaber ◽  
Zeshan Mahmud Chowdhury ◽  
Arittra Bhattacharjee ◽  
Muntahi Mourin ◽  
Chaman Ara Keya ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Envelope Protein ◽  
Docking Simulation ◽  
E Proteins ◽  
Molecular Docking Simulation ◽  
Dynamics Simulations ◽  
Molecular Docking And Dynamics ◽  
Do So ◽  
Amiloride Analogs

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes small envelope protein (E) that plays a major role in viral assembly, release, pathogenesis, and host inflammation. Previous studies demonstrated that pyrazine ring containing amiloride analogs inhibit this protein in different types of coronavirus including SARS-CoV-1 small envelope protein E (SARS-CoV-1 E). SARS-CoV-1 E has 93.42% sequence identity with SARS-CoV-2 E and shared a conserved domain NS3/small envelope protein (NS3_envE). Amiloride analog hexamethylene amiloride (HMA) can inhibit SARS-CoV-1 E. Therefore, we performed molecular docking and dynamics simulations to explore whether amiloride analogs are effective in inhibiting SARS-CoV-2 E. To do so, SARS-CoV-1 E and SARS-CoV-2 E proteins were taken as receptors while HMA and 3-amino-5-(azepan-1-yl)-N-(diaminomethylidene)-6-pyrimidin-5-ylpyrazine-2-carboxamide (3A5NP2C) were selected as ligands. Molecular docking simulation showed higher binding affinity scores of HMA and 3A5NP2C for SARS-CoV-2 E than SARS-CoV-1 E. Moreover, HMA and 3A5NP2C engaged more amino acids in SARS-CoV-2 E. Molecular dynamics (MD) simulation for 1 μs (1,000 ns) revealed that these ligands could alter the native structure of the proteins and their flexibility. Our study suggests that suitable amiloride analogs might yield a prospective drug against coronavirus disease 2019.

scholarly journals Virtual Repurposing of Ursodeoxycholate and Chenodeoxycholate as Lead Candidates Against SARS-Cov2-Envelope Protein: A Molecular Dynamics Investigation

2020 ◽  
Author(s):  
Reena Yadav ◽  
chinmayee choudhury ◽  
Yashwant Kumar ◽  
Alka Bhatia
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Envelope Protein ◽  
Homology Modelling ◽  
Protein A ◽  
Drug Repurposing ◽  
Dynamics Simulations ◽  
Global Threat ◽  
Polar Functional Groups

Drug repurposing is an apt choice to combat the currently prevailing global threat of COVID-19, caused by SARS-Cov2 in absence of any specific medication/vaccine. The present work attempts to computationally evaluate binding affinities and effect of two widely used surfactant drugs i.e. chenodeoxycholate (CDC) and ursodeoxycholate (UDC) with the envelope protein of SARS-Cov2 (SARS-Cov2-E) using homology modelling, molecular docking and molecular dynamics simulations. A good quality homo-pentameric structure of SARS-Cov2-E was modelled from its homologue with more than 90% sequence identity followed by symmetric docking. The pentameric structure was embedded in a DPPC membrane and subsequently energy minimized. The minimized structure was used for blind molecular docking of CDC and UDC to obtain the best scoring SARS-Cov2-E–CDC/UDC complexes, which were subjected to 230ns molecular dynamics simulations in triplicates in DPPC membrane environment. Comparative analyses of structural and enthalpic properties and molecular interaction profiles from the MD trajectories revealed that, both CDC and UDC could stably bind to SARS-Cov2-E through H-bonds, water-bridges and hydrophobic contacts in the transmembraneresidues.T30 was observed to be a key residue for CDC/UDC binding. The polar functional groups of the bound CDC/UDC facilitated entry of a large number of water molecules into the channel and affected the H-bonding pattern between adjacent monomeric chains, loosening the compact transmembrane region of SARS-Cov2-E. These observations suggest the potential of CDC/UDC as repurposed candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitate entry of solvents/polar inhibitors inside the viral cell.

scholarly journals DMAG, a Novel Countermeasure for the Treatment of Thrombocytopenia

2021 ◽  
Author(s):  
Jing Lin ◽  
Jing Zeng ◽  
Sha Liu ◽  
Xin Shen ◽  
Nan Jiang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Kegg Pathway ◽  
Docking Simulation ◽  
Dynamics Simulation ◽  
Network Pharmacology ◽  
Molecular Docking Simulation ◽  
The Core ◽  
Hel Cells ◽  
Megakaryocyte Differentiation

Abstract Background: Thrombocytopenia is one of the most common hematological disease that can be life-threatening caused by bleeding complications. However, the treatment options for thrombocytopenia remain limited. Methods: In this study, giemsa staining, phalloidin staining and flow cytometry were firstly used to identify the effects of 3,3'-Di-O-methylellagic acid 4'-glucoside (DMAG), a natural ellagic acid derived from Sanguisorba officinalis L. (SOL) on megakaryocyte differentiation in HEL cells. Then, thrombocytopenia mice model was constructed by X-ray irradiation to evaluate the therapeutic action of DMAG on thrombocytopenia. Next, network pharmacology approachs were carried out to identify the targets of DMAG. Moreover, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrich-ment analyses were performed to elucidate the underling mechanism of DMAG against thrombocytopenia. Finally, Molecular docking simulation, molecular dynamics simulation and western blot analysis were used to explore the relationship between DAMG with its targets.Results: DMAG significantly promoted megakaryocyte differentiation and maturation of HEL cells. DMAG administration accelerated platelet recovery and megakaryopoiesis in thrombocytopenia mice. Network pharmacology revealed that ITGA2B, ITGB3, VWF, PLEK, TLR2, BCL2, BCL2L1 and TNF were the core targets of DMAG. GO and KEGG pathway enrichment analyses suggested that the core targets of DMAG were enriched in PI3K-Akt signaling pathway, hematopoietic cell lineage, ECM-receptor interaction and platelet activation. Molecular docking simulation and molecular dynamics simulation further indicated that ITGA2B, ITGB3, PLEK and TLR2 displayed strong binding ability with DMAG. Finally, western blot analysis evidenced that DMAG up-regulated the expression of ITGA2B, ITGB3, VWF and PLEK. Conclusion: DMAG plays a critical role in promoting megakaryocytes differentiation and platelets production and might be a promising medicine for the treatment of thrombocytopenia.

scholarly journals Virtual Repurposing of Ursodeoxycholate and Chenodeoxycholate as Lead Candidates Against SARS-Cov2-Envelope Protein: A Molecular Dynamics Investigation

2020 ◽  
Author(s):  
Reena Yadav ◽  
chinmayee choudhury ◽  
Yashwant Kumar ◽  
Alka Bhatia
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Envelope Protein ◽  
Homology Modelling ◽  
Protein A ◽  
Drug Repurposing ◽  
Dynamics Simulations ◽  
Global Threat ◽  
Polar Functional Groups

Drug repurposing is an apt choice to combat the currently prevailing global threat of COVID-19, caused by SARS-Cov2 in absence of any specific medication/vaccine. The present work attempts to computationally evaluate binding affinities and effect of two widely used surfactant drugs i.e. chenodeoxycholate (CDC) and ursodeoxycholate (UDC) with the envelope protein of SARS-Cov2 (SARS-Cov2-E) using homology modelling, molecular docking and molecular dynamics simulations. A good quality homo-pentameric structure of SARS-Cov2-E was modelled from its homologue with more than 90% sequence identity followed by symmetric docking. The pentameric structure was embedded in a DPPC membrane and subsequently energy minimized. The minimized structure was used for blind molecular docking of CDC and UDC to obtain the best scoring SARS-Cov2-E–CDC/UDC complexes, which were subjected to 230ns molecular dynamics simulations in triplicates in DPPC membrane environment. Comparative analyses of structural and enthalpic properties and molecular interaction profiles from the MD trajectories revealed that, both CDC and UDC could stably bind to SARS-Cov2-E through H-bonds, water-bridges and hydrophobic contacts in the transmembraneresidues.T30 was observed to be a key residue for CDC/UDC binding. The polar functional groups of the bound CDC/UDC facilitated entry of a large number of water molecules into the channel and affected the H-bonding pattern between adjacent monomeric chains, loosening the compact transmembrane region of SARS-Cov2-E. These observations suggest the potential of CDC/UDC as repurposed candidates to hinder the survival of SARS-Cov2 by disrupting the structure of SARS-Cov2-E and facilitate entry of solvents/polar inhibitors inside the viral cell.

Promising inhibitors of nsp2 of CHIKV using molecular docking and temperature-dependent molecular dynamics simulations

2021 ◽  
pp. 1-9
Author(s):  
Mahendera Kumar Meena ◽  
Durgesh Kumar ◽  
Kamlesh Kumari ◽  
Nagendra Kumar Kaushik ◽  
Rammapa Venkatesh Kumar ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulations ◽  
Temperature Dependent ◽  
Dynamics Simulations

Design, Molecular docking, Synthesis and Biological evaluation of 5, 7 dimethyl pyrido(2, 3-d)pyrimidin-4-one and 4,5 dihydro pyrazolo (3, 4-d) pyrimidines for cytotoxic activity

2021 ◽  
pp. 3029-3038
Author(s):  
M. Sathish Kumar ◽  
M. Vijey Aanandhi
Keyword(s):  
Molecular Docking ◽  
Docking Simulation ◽  
Docking Studies ◽  
Biological Evaluation ◽  
Hep G2 ◽  
Molecular Docking Simulation ◽  
Hela Cell Lines ◽  
Benzene Diazonium ◽  
Synthesis And Biological Evaluation ◽  
Mcf 7

The fused pyrimidine derivatives are potent tyrosine kinase and thymidylate synthase inhibitors. The compound 3-(4-sulphonyl amino)-2-methyl thio-6-phenyl azo-5, 7-dimethyl pyrido(2,3-d)pyrimidin-4-one was synthesized from Ethyl 2-amino-4,6-dimethylpyridine-3-carboxylate, benzene diazonium chloride, benzene sulphonyl amino isothiocyanate in subsequent reactions. 1-(1, 3-benzothiazol-2-yl)-3-methyl-4-phenyl-1H-pyrazolo[3,4-d]pyrimidines were synthesized from 1, 3-benzothiazole, 2-thiol, Hydrazine Hydrate, 2-hydrazinyl-1, 3-benzothiazole and aldehydes in subsequent reactions. Twenty-five derivatives pyrimidine scaffolds were designed and performed molecular docking studies for the ability to inhibit the target protein using molecular docking simulation, selective compounds were synthesized and characterized by spectral methods. All the synthesized compounds evaluated for their antioxidant activity and MTT assay exhibited compounds 13c, 13e and 14d can be potential anticancer candidates against MCF-7, Hep G2 and Hela cell lines respectively. Based on all the studies conclude that good agreement was observed between the top-ranked docking scores and top experimental inhibitors when compared with standards ascorbic acid and imatinib. Hence, the compounds could be considered as new anticancer hits for further lead optimization.

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