scholarly journals Discovery of [1,2,4]Triazole Derivatives as New Metallo-β-Lactamase Inhibitors

Molecules ◽  
2019 ◽  
Vol 25 (1) ◽  
pp. 56
Author(s):  
Chen Yuan ◽  
Jie Yan ◽  
Chen Song ◽  
Fan Yang ◽  
Chao Li ◽  
...  
Keyword(s):  
Public Health ◽  
Molecular Docking ◽  
Active Site ◽  
Inhibitory Concentration ◽  
Hydrophobic Interactions ◽  
Global Public Health ◽  
Triazole Derivatives ◽  
Potent Inhibition ◽  
Zinc Coordination

The emergence and spread of metallo-β-lactamase (MBL)-mediated resistance to β-lactam antibacterials has already threatened the global public health. A clinically useful MBL inhibitor that can reverse β-lactam resistance has not been established yet. We here report a series of [1,2,4]triazole derivatives and analogs, which displayed inhibition to the clinically relevant subclass B1 (Verona integron-encoded MBL-2) VIM-2. 3-(4-Bromophenyl)-6,7-dihydro-5H-[1,2,4]triazolo [3,4-b][1,3]thiazine (5l) manifested the most potent inhibition with an IC50 (half-maximal inhibitory concentration) value of 38.36 μM. Investigations of 5l against other B1 MBLs and the serine β-lactamases (SBLs) revealed the selectivity to VIM-2. Molecular docking analyses suggested that 5l bound to the VIM-2 active site via the triazole involving zinc coordination and made hydrophobic interactions with the residues Phe61 and Tyr67 on the flexible L1 loop. This work provided new triazole-based MBL inhibitors and may aid efforts to develop new types of inhibitors combating MBL-mediated resistance.

scholarly journals The structure of the metallo-β-lactamase VIM-2 in complex with a triazolylthioacetamide inhibitor

2016 ◽  
Vol 72 (11) ◽  
pp. 813-819 ◽  
Author(s):  
Tony Christopeit ◽  
Ke-Wu Yang ◽  
Shao-Kang Yang ◽  
Hanna-Kirsti S. Leiros
Keyword(s):  
Public Health ◽  
Crystal Structure ◽  
Active Site ◽  
Drug Target ◽  
Zinc Ions ◽  
Clinical Use ◽  
Global Public Health ◽  
Promising Strategy ◽  
Conserved Residue ◽  
Substrate Spectrum

The increasing number of pathogens expressing metallo-β-lactamases (MBLs), and in this way achieving resistance to β-lactam antibiotics, is a significant threat to global public health. A promising strategy to treat such resistant pathogens is the co-administration of MBL inhibitors together with β-lactam antibiotics. However, an MBL inhibitor suitable for clinical use has not yet been identified. Verona integron-encoded metallo-β-lactamase 2 (VIM-2) is a widespread MBL with a broad substrate spectrum and hence is an interesting drug target for the treatment of β-lactam-resistant infections. In this study, three triazolylthioacetamides were tested as inhibitors of VIM-2. One of the tested compounds showed clear inhibition of VIM-2, with an IC50of 20 µM. The crystal structure of the inhibitor in complex with VIM-2 was obtained by DMSO-free co-crystallization and was solved at a resolution of 1.50 Å. To our knowledge, this is the first structure of a triazolylthioacetamide inhibitor in complex with an MBL. Analysis of the structure shows that the inhibitor binds to the two zinc ions in the active site of VIM-2 and revealed detailed information on the interactions involved. Furthermore, the crystal structure showed that binding of the inhibitor induced a conformational change of the conserved residue Trp87.

scholarly journals Molecular docking and pharmacokinetic screening of eucalyptol (1,8 cineole) from eucalyptus essential oil against SARS-CoV-2

2020 ◽  
Vol 12 (3) ◽  
pp. 536-545
Author(s):  
Arun D. SHARMA ◽  
Inderjeet KAUR
Keyword(s):  
Molecular Docking ◽  
Essential Oil ◽  
Active Site ◽  
In Silico ◽  
Hydrophobic Interactions ◽  
Rna Virus ◽  
In Silico Analysis ◽  
Active Site Residues ◽  
Virus Family

SARS-CoV-2 (COVID-19), member of corona virus family, is a positive single stranded RNA virus. Due to lack of drugs it is spreading its tentacles across the world. Being associated with cough, fever, and respiratory distress, this disease caused more than 15% mortality worldwide. Mpro/3CLpro has recently been regarded as a suitable target for drug design due to its vital role in virus replication. The current study focused on the inhibitory activity of eucalyptol (1,8 cineole), an essential oil component from eucalyptus oil, against Mpro/3CLprofrom SARS-CoV-2. Till date there is no work is undertaken on in-silico analysis of this compound against Mpro/3CLproof SARS-CoV-2. Molecular docking studies were conducted by using 1-click dock tool and Patchdock analysis. In-silico absorption, distribution, metabolism, excretion and toxicity (ADMET) profile were also studied. The calculated parameters such as docking score indicated effective binding of eucalyptol to COVID-19 Mpro protein. Active site prediction revealed the involvement of active site residues in ligand binding. Interactions results indicated that, Mpro/3CLpro/eucalyptol complexes forms hydrophobic interactions. ADMET studies provided guidelines and mechanistic scope for identification of potent anti-COVID 19 drug. Therefore, eucalyptol may represent potential herbal treatment to act as COVID-19 Mpro/3CLproinhibitor, a finding which must be validated in vivo.

scholarly journals Canthin-6-One 9-O-Beta-Glucopyranoside: an inhibitor of SARS-CoV-2 (COVID 19) proteases PLpro and Mpro/ 3CLpro

2020 ◽  
Author(s):  
Devvret Verma ◽  
Debasis Mitra ◽  
Anshul Kamboj ◽  
Bhaswatimayee Mahakur ◽  
Priya Chaudhary ◽  
...  
Keyword(s):  
Public Health ◽  
Molecular Docking ◽  
Binding Energy ◽  
Public Health Issue ◽  
Global Public Health ◽  
Sophora Flavescens ◽  
Main Protease ◽  
Rapid Spread ◽  
Brain Barrier Permeability ◽  
Gi Absorption

Abstract The rapid spread of SARS-CoV-2 has raised a severe global public health issue, where therapy is not identified with specific drugs or vaccines. The present investigation dealt with the inhibition of various proteins and receptors of virus using phytocompounds of three pertinent medicinal plants i.e. Eurycoma harmandiana, Sophora flavescens and Andrographis paniculata. Phytocompounds known to have antiviral properties were screened against the papain-like protease (PLpro) and main protease (Mpro) / 3-chymotrypsin-like Protease (3CLpro). Molecular docking with Canthin-6-One 9-O-Beta-Glucopyranoside showed the highest binding affinity and least binding energy with both the proteases viz. PLpro and Mpro/ 3CLpro. ADMET analysis of the compound suggested that it is having drug-like properties like high gastrointestinal (gi-) absorption, no blood-brain barrier permeability, and high lipophilicity.

scholarly journals Anti-tick effect and cholinesterase inhibition caused by Prosopis juliflora alkaloids: in vitro and in silico studies

2020 ◽  
Vol 29 (2) ◽  
Author(s):  
Hélimar Gonçalves de Lima ◽  
Francianne Oliveira Santos ◽  
Acidália Carine Vieira Santos ◽  
Gisele Dias da Silva ◽  
Rafaela Jesus dos Santos ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Inhibitory Concentration ◽  
Interaction Mechanism ◽  
Docking Studies ◽  
Prosopis Juliflora ◽  
Cholinesterase Inhibition ◽  
In Silico Studies ◽  
Pi Interactions

Abstract We investigated the in vitro acaricide activity of the methanolic extract (ME) and alkaloid-rich fraction (AF) of Prosopis juliflora on Rhipicephalus microplus and correlated this effect with acetylcholinesterase (AChE) inhibition. The acaricide activity was evaluated using adult and larval immersion tests. Also, we studied the possible interaction mechanism of the major alkaloids present in this fraction via molecular docking at the active site of R. microplus AChE1 (RmAChE1). Higher reproductive inhibitory activity of the AF was recorded, with effective concentration (EC50) four times lower than that of the ME (31.6 versus 121 mg/mL). The AF caused mortality of tick larvae, with lethal concentration 50% (LC50) of 13.8 mg/mL. Both ME and AF were seen to have anticholinesterase activity on AChE of R. microplus larvae, while AF was more active with half-maximal inhibitory concentration (IC50) of 0.041 mg/mL. The LC-MS/MS analyses on the AF led to identification of three alkaloids: prosopine (1), juliprosinine (2) and juliprosopine (3). The molecular docking studies revealed that these alkaloids had interactions at the active site of the RmAChE1, mainly relating to hydrogen bonds and cation-pi interactions. We concluded that the alkaloids of P. juliflora showed acaricide activity on R. microplus and acted through an anticholinesterase mechanism.

scholarly journals Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2

2020 ◽  
Author(s):  
Vaishali Chandel ◽  
Prem Prakash Sharma ◽  
Sibin Raj ◽  
Brijesh Rathi ◽  
Dhruv Kumar
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Binding Energy ◽  
Active Site ◽  
Hydrophobic Interactions ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Structural Protein ◽  
Maximum Stability ◽  
Spike Proteins

<p>Due to unavailability of therapeutic approach for the novel coronavirus disease (COVID-19), the drug repurposing approach would be the fastest and efficient way of drug development against this deadly disease. We have applied bioinformatics approach for structure-based drug repurposing to identify the potential inhibitors through drug screening, molecular docking and molecular dynamics against non-structural protein 9 (Nsp9) replicase and spike proteins of the SARS-CoV-2 from the FDA approved drugs. We have performed virtual screening of 2000 FDA approved compounds including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis and active phytochemicals against Nsp9 replicase and spike proteins of SARS-CoV-2. Molecular docking was performed using Autodock-Vina. Selected hit compounds were identified based on their highest binding energy and favourable ADME profile. Notably, Conivaptan, an arginine vasopressin antagonist drug exhibited highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present on the active site of Nsp9 replicase. Additionally, Tegobuvir, a non-nucleoside inhibitor of hepatitis C virus exhibited maximum stability with highest binding energy (-8.1 Kcal/mol) on the active site of spike protein. Molecular docking scores were further validated with the molecular dynamics using Schrodinger, which supported strong stability of ligands with proteins at their active site through water bridges, hydrophobic interactions, H-bond. Overall, our findings highlight the fact that Conivaptan and Tegobuvir could be used to control the infection and propagation of SARS-CoV-2 targeting Nsp9 replicase and spike protein, respectively. Moreover, <i>in vitro</i> and <i>in vivo</i> validation of these findings will be helpful in bringing these molecules at the clinical settings.</p>

scholarly journals Inhibition of ADAM17/TACE activity by zinc-chelating rye secalin-derived tripeptides and analogues

RSC Advances ◽  
2017 ◽  
Vol 7 (42) ◽  
pp. 26361-26369 ◽  
Author(s):  
M. Chinonye Udechukwu ◽  
Apollinaire Tsopmo ◽  
Hannah Mawhinney ◽  
Rong He ◽  
Petra C. Kienesberger ◽  
...  
Keyword(s):  
Hydrogen Bonds ◽  
Active Site ◽  
Hydrophobic Interactions ◽  
Zinc Coordination

Rye secalin-derived cysteine-containing tripeptides and analogues inhibited ADAM17 activity via active site zinc coordination, hydrogen bonds and hydrophobic interactions.

scholarly journals Structure Based Drug Repurposing Through Targeting Nsp9 Replicase and Spike Proteins of SARS-CoV-2

2020 ◽  
Author(s):  
Vaishali Chandel ◽  
Prem Prakash Sharma ◽  
Sibin Raj ◽  
Brijesh Rathi ◽  
Dhruv Kumar
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Binding Energy ◽  
Active Site ◽  
Hydrophobic Interactions ◽  
Drug Repurposing ◽  
Spike Protein ◽  
Structural Protein ◽  
Maximum Stability ◽  
Spike Proteins

<p>Due to unavailability of therapeutic approach for the novel coronavirus disease (COVID-19), the drug repurposing approach would be the fastest and efficient way of drug development against this deadly disease. We have applied bioinformatics approach for structure-based drug repurposing to identify the potential inhibitors through drug screening, molecular docking and molecular dynamics against non-structural protein 9 (Nsp9) replicase and spike proteins of the SARS-CoV-2 from the FDA approved drugs. We have performed virtual screening of 2000 FDA approved compounds including antiviral, anti-malarial, anti-parasitic, anti-fungal, anti-tuberculosis and active phytochemicals against Nsp9 replicase and spike proteins of SARS-CoV-2. Molecular docking was performed using Autodock-Vina. Selected hit compounds were identified based on their highest binding energy and favourable ADME profile. Notably, Conivaptan, an arginine vasopressin antagonist drug exhibited highest binding energy (-8.4 Kcal/mol) and maximum stability with the amino acid residues present on the active site of Nsp9 replicase. Additionally, Tegobuvir, a non-nucleoside inhibitor of hepatitis C virus exhibited maximum stability with highest binding energy (-8.1 Kcal/mol) on the active site of spike protein. Molecular docking scores were further validated with the molecular dynamics using Schrodinger, which supported strong stability of ligands with proteins at their active site through water bridges, hydrophobic interactions, H-bond. Overall, our findings highlight the fact that Conivaptan and Tegobuvir could be used to control the infection and propagation of SARS-CoV-2 targeting Nsp9 replicase and spike protein, respectively. Moreover, <i>in vitro</i> and <i>in vivo</i> validation of these findings will be helpful in bringing these molecules at the clinical settings.</p>

scholarly journals Eucalyptol (1,8 cineole) from Eucalyptus Essential Oil a Potential Inhibitor of COVID 19 Corona Virus Infection by Molecular Docking Studies

2020 ◽  
Author(s):  
Arun Dev Sharma ◽  
inderjeet kaur
Keyword(s):  
Molecular Docking ◽  
Essential Oil ◽  
Active Site ◽  
Hydrophobic Interactions ◽  
Rna Virus ◽  
Docking Studies ◽  
Active Site Residues ◽  
Virus Family ◽  
Molecular Docking Studies ◽  
Corona Virus

Background: COVID-19, a member of corona virus family is spreading its tentacles across the world due to lack of drugs at present. Associated with its infection are cough, fever and respiratory problems causes more than 15% mortality worldwide. It is caused by a positive, single stranded RNA virus from the enveloped coronaviruse family. However, the main viral proteinase (Mpro/3CLpro) has recently been regarded as a suitable target for drug design against SARS infection due to its vital role in polyproteins processing necessary for coronavirus reproduction.Objectives: The present in silico study was designed to evaluate the effect of Eucalyptol (1,8 cineole), a essential oil component from eucalyptus oil, on Mpro by docking study.Methods: In the present study, molecular docking studies were conducted by using 1-click dock and swiss dock tools. Protein interaction mode was calculated by Protein Interactions Calculator.Results: The calculated parameters such as RMSD, binding energy, and binding site similarity indicated effective binding of eucalyptol to COVID-19 proteinase. Active site prediction further validated the role of active site residues in ligand binding. PIC results indicated that, Mpro/eucalyptol complexes forms hydrophobic interactions, hydrogen bond interactions and strong ionic interactions.Conclusions: Therefore, eucalyptol may represent potential treatment potential to act as COVID-19 Mpro inhibitor. However, further research is necessary to investigate their potential medicinal use.

scholarly journals Monosubstituted Acetophenone Thiosemicarbazones as Potent Inhibitors of Tyrosinase: Synthesis, Inhibitory Studies, and Molecular Docking

2021 ◽  
Vol 14 (1) ◽  
pp. 74
Author(s):  
Katarzyna Hałdys ◽  
Waldemar Goldeman ◽  
Natalia Anger-Góra ◽  
Joanna Rossowska ◽  
Rafał Latajka
Keyword(s):  
Molecular Docking ◽  
Active Site ◽  
Melanoma Cell Line ◽  
Inhibitory Concentration ◽  
Copper Ions ◽  
Tyrosinase Inhibitor ◽  
Melanin Production ◽  
B16f10 Cells ◽  
Tyrosinase Inhibitors ◽  
Murine Melanoma Cell Line

A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions between the enzyme and the inhibitors, molecular docking to the active site was performed. TSCs 5, 6, 8, and 9 revealed a half maximal inhibitory concentration (IC50) below 1 µM. Compound 6 turned out to be the most potent tyrosinase inhibitor. All investigated compounds showed reversible inhibition of competitive or mixed type. The para-substituted TSCs had higher affinity for the enzyme as compared to their ortho- and meta-analogues. All investigated compounds inhibited melanin production in B16F10 cells at the micromolar level. Molecular docking showed that the sulfur atom of the thiourea moiety penetrates the active site and interacts with copper ions. The above outcomes might be helpful in the design of new tyrosinase inhibitors in the food and cosmetic industries.

scholarly journals Anti-TB Evaluation of Novel 2,3-Dihydroquinazolin-4(1H)-Ones and in Silico Studies of The Active Compounds

2021 ◽  
Author(s):  
Apurba Dutta ◽  
Priyanka Trivedi ◽  
Dipshikha Gogoi ◽  
Pankaj Chetia ◽  
Vinita Chaturvedi ◽  
...  
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Molecular Docking ◽  
Minimum Inhibitory Concentration ◽  
Active Site ◽  
In Silico ◽  
Inhibitory Concentration ◽  
Acyl Carrier Protein ◽  
Carrier Protein ◽  
In Silico Studies

Abstract In vitro anti-tubercular activity of a series of 15 novel 2,3-dihydroquinazolin-4(1H)-one analogues were evaluated against Mycobacterium tuberculosis H37Ra (ATCC 25177 strain). Among the series, seven compounds showed moderate to good anti-TB activity with minimum inhibitory concentration (MIC) values ranging from 25.0-12.5 μg/mL. Further, in silico experiments were carried out to identify the probable ligand-protein interaction. Molecular docking of the target compounds into the active site of enzymes 1DQY Antigen 85C from Mycobacterium Tuberculosis and 2NSD Enoyl Acyl Carrier Protein Reductase reveals notable information on the possible binding interactions.

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