scholarly journals THE INTERACTION OF PROTONATED OCTOPAMINE AND NOREPINEPHRINE WITH Β1-ADRENERGIC RECEPTOR: MOLECULAR DOCKING AND DYNAMICAL SIMULATION

2020 ◽  
pp. 13-25
Author(s):  
Žiko Milanović ◽  
Dušan Dimić ◽  
Jasmina Dimitrić Marković ◽  
Marijana Stanojević-Pirković ◽  
Edina Avdović ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Adrenergic Receptor ◽  
Md Simulations ◽  
Protonated Form ◽  
Free Energy Calculations ◽  
Amino Acid Residues ◽  
Salt Bridges ◽  
Docking Simulations ◽  
Dynamical Simulation ◽  
G Protein Coupled

In the current study, the interaction mechanisms between protonated neurotransmitters: octopamine (4-(2-amino-1-hydroxyethyl)phenol) and norepinephrine (4-[(1R)-2-amino-1-hydroxyethyl]benzene-1,2-diol) with the β-1 adrenergic receptor (β1AR) were examined by molecular docking, molecular dynamics (MD) simulations and MM/PBSA free energy calculations. The investigated receptor belongs to the G-protein coupled receptor group. The investigation was carried out at physiological pH=7.4. It was estimated that both compounds exist in the protonated form in the water at physiological pH. It was found that both protonated neurotransmitters established similar interactions with amino acid residues of the receptor, such as salt bridges, conventional hydrogen bonds, π-σ, and T-shaped π-π interactions, as shown by molecular docking simulations. As the initial structures for MD simulation with a total time of 10ns the most stable docking structures were used. The presented results are expected to provide some useful information for the design of specific β1AR agonists.

scholarly journals Molecular docking-based test for affinities of two ligands toward vasopressin and oxytocin receptors.

2001 ◽  
Vol 48 (1) ◽  
pp. 131-135 ◽  
Author(s):  
R Slusarz ◽  
R Kaźmierkiewicz ◽  
A Giełdoń ◽  
B Lammek ◽  
J Ciarkowski
Keyword(s):  
Molecular Docking ◽  
Amino Acid ◽  
Ligand Binding ◽  
Effective Procedure ◽  
Amino Acid Residues ◽  
Receptor Ligand ◽  
Docking Simulations ◽  
Oxytocin Receptors ◽  
Developing Area

Molecular docking simulations are now fast developing area of research. In this work we describe an effective procedure of preparation of the receptor-ligand complexes. The amino-acid residues involved in ligand binding were identified and described.

scholarly journals Computational Exploration for Lead Compounds That Can Reverse the Nuclear Morphology in Progeria

2017 ◽  
Vol 2017 ◽  
pp. 1-15 ◽  
Author(s):  
Shailima Rampogu ◽  
Ayoung Baek ◽  
Minky Son ◽  
Amir Zeb ◽  
Chanin Park ◽  
...  
Keyword(s):  
Binding Free Energy ◽  
Genetic Disorder ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Premature Aging ◽  
Farnesyltransferase Inhibitors ◽  
Docking Simulations ◽  
Lipinski’S Rule ◽  
Computational Exploration ◽  
The Stability

Progeria is a rare genetic disorder characterized by premature aging that eventually leads to death and is noticed globally. Despite alarming conditions, this disease lacks effective medications; however, the farnesyltransferase inhibitors (FTIs) are a hope in the dark. Therefore, the objective of the present article is to identify new compounds from the databases employing pharmacophore based virtual screening. Utilizing nine training set compounds along with lonafarnib, a common feature pharmacophore was constructed consisting of four features. The validated Hypo1 was subsequently allowed to screen Maybridge, Chembridge, and Asinex databases to retrieve the novel lead candidates, which were then subjected to Lipinski’s rule of 5 and ADMET for drug-like assessment. The obtained 3,372 compounds were forwarded to docking simulations and were manually examined for the key interactions with the crucial residues. Two compounds that have demonstrated a higher dock score than the reference compounds and showed interactions with the crucial residues were subjected to MD simulations and binding free energy calculations to assess the stability of docked conformation and to investigate the binding interactions in detail. Furthermore, this study suggests that the Hits may be more effective against progeria and further the DFT studies were executed to understand their orbital energies.

scholarly journals Effectiveness of Natural Antioxidants against SARS-CoV-2? Insights from the In-Silico World

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1011
Author(s):  
Muhammad Fayyaz ur Rehman ◽  
Shahzaib Akhter ◽  
Aima Iram Batool ◽  
Zeliha Selamoglu ◽  
Mustafa Sevindik ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Protein Interactions ◽  
Dissociation Constants ◽  
Antiviral Agents ◽  
Natural Antioxidants ◽  
Md Simulations ◽  
Binding Energies ◽  
Protein Targets ◽  
Docking Simulations ◽  
Main Protease

The SARS CoV-2 pandemic has affected millions of people around the globe. Despite many efforts to find some effective medicines against SARS CoV-2, no established therapeutics are available yet. The use of phytochemicals as antiviral agents provides hope against the proliferation of SARS-CoV-2. Several natural compounds were analyzed by virtual screening against six SARS CoV-2 protein targets using molecular docking simulations in the present study. More than a hundred plant-derived secondary metabolites have been docked, including alkaloids, flavonoids, coumarins, and steroids. SARS CoV-2 protein targets include Main protease (MPro), Papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), Spike glycoprotein (S), Helicase (Nsp13), and E-Channel protein. Phytochemicals were evaluated by molecular docking, and MD simulations were performed using the YASARA structure using a modified genetic algorithm and AMBER03 force field. Binding energies and dissociation constants allowed the identification of potentially active compounds. Ligand-protein interactions provide an insight into the mechanism and potential of identified compounds. Glycyrrhizin and its metabolite 18-β-glycyrrhetinic acid have shown a strong binding affinity for MPro, helicase, RdRp, spike, and E-channel proteins, while a flavonoid Baicalin also strongly binds against PLpro and RdRp. The use of identified phytochemicals may help to speed up the drug development and provide natural protection against SARS-CoV-2.

scholarly journals Insight Derived from Molecular Docking and Molecular Dynamics Simulations into the Binding Interactions Between HIV-1 Protease Inhibitors and SARS-CoV-2 3CLpro

2020 ◽  
Author(s):  
peng sang ◽  
Shuhui Tian ◽  
Zhaohui Meng ◽  
Liquan Yang
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Binding Affinity ◽  
Proteinase Inhibitors ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Respiratory Illness ◽  
Free Energy Calculations ◽  
Binding Interactions ◽  
Hiv 1

<p>A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified from respiratory illness patients in Wuhan, Hubei Province, China, which has recently emerged as a serious threat to the world public health. Hower, no approved drugs have been found to effectively inhibit the virus. Since it has been reported that the HIV-1 protease inhibitors can be used as anti-SARS drugs by tegarting SARS-CoV 3CLpro, we choose six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro, and to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID19) caused by SARS-CoV-2 infection. The molecular docking results indicate that, the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than its SARS homologue. Two docking complexes (indinavir and darunavir) with high docking scores were futher subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two proteinase inhibitors and the 3CLpro. Our results show that darunavir has the best binding affinity with SARS-CoV-2 and SARS-CoV 3CLpro among all inhibitors, indicating it has the potential to become an anti-COVID-19 clinical drug. The likely reason behind the increased binding affinity of HIV-1 protease inhibitors toward SARS-CoV2 3CLpro than that of SARS-CoV were investigated by MD simulations. Our study provides insight into the possible role of structural flexibility during interactions between 3CLpro and inhibitors, and sheds light on the structure-based design of anti-COVID-19 drugs targeting the SARS-CoV-2 3CLpro. </p><div><br></div>

scholarly journals Insight Derived from Molecular Docking and Molecular Dynamics Simulations into the Binding Interactions Between HIV-1 Protease Inhibitors and SARS-CoV-2 3CLpro

2020 ◽  
Author(s):  
peng sang ◽  
Shuhui Tian ◽  
Zhaohui Meng ◽  
Liquan Yang
Keyword(s):  
Molecular Docking ◽  
Protease Inhibitors ◽  
Binding Affinity ◽  
Proteinase Inhibitors ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Respiratory Illness ◽  
Free Energy Calculations ◽  
Binding Interactions ◽  
Hiv 1

<p>A novel severe acute respiratory syndrome coronavirus (SARS-CoV-2) was identified from respiratory illness patients in Wuhan, Hubei Province, China, which has recently emerged as a serious threat to the world public health. Hower, no approved drugs have been found to effectively inhibit the virus. Since it has been reported that the HIV-1 protease inhibitors can be used as anti-SARS drugs by tegarting SARS-CoV 3CLpro, we choose six approved anti-HIV-1 drugs to investigate their binding interactions between 3CLpro, and to evaluate their potential to become clinical drugs for the new coronavirus pneumonia (COVID19) caused by SARS-CoV-2 infection. The molecular docking results indicate that, the 3CLpro of SARS-CoV-2 has a higher binding affinity for all the studied inhibitors than its SARS homologue. Two docking complexes (indinavir and darunavir) with high docking scores were futher subjected to MM-PBSA binding free energy calculations to detail the molecular interactions between these two proteinase inhibitors and the 3CLpro. Our results show that darunavir has the best binding affinity with SARS-CoV-2 and SARS-CoV 3CLpro among all inhibitors, indicating it has the potential to become an anti-COVID-19 clinical drug. The likely reason behind the increased binding affinity of HIV-1 protease inhibitors toward SARS-CoV2 3CLpro than that of SARS-CoV were investigated by MD simulations. Our study provides insight into the possible role of structural flexibility during interactions between 3CLpro and inhibitors, and sheds light on the structure-based design of anti-COVID-19 drugs targeting the SARS-CoV-2 3CLpro. </p><div><br></div>

scholarly journals Sialic acid mediated mechanical activation of β2 adrenergic receptors by bacterial pili

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Zoe Virion ◽  
Stéphane Doly ◽  
Kusumika Saha ◽  
Mireille Lambert ◽  
François Guillonneau ◽  
...  
Keyword(s):  
Sialic Acid ◽  
Mechanical Activation ◽  
Adrenergic Receptor ◽  
Molecular Mechanisms ◽  
Receptor Activation ◽  
Neuraminic Acid ◽  
Amino Acid Residues ◽  
Species Selectivity ◽  
G Protein Coupled ◽  
Specific Distance

Abstract Meningococcus utilizes β-arrestin selective activation of endothelial cell β2 adrenergic receptor (β2AR) to cause meningitis in humans. Molecular mechanisms of receptor activation by the pathogen and of its species selectivity remained elusive. We report that β2AR activation requires two asparagine-branched glycan chains with terminally exposed N-acetyl-neuraminic acid (sialic acid, Neu5Ac) residues located at a specific distance in its N-terminus, while being independent of surrounding amino-acid residues. Meningococcus triggers receptor signaling by exerting direct and hemodynamic-promoted traction forces on β2AR glycans. Similar activation is recapitulated with beads coated with Neu5Ac-binding lectins, submitted to mechanical stimulation. This previously unknown glycan-dependent mode of allosteric mechanical activation of a G protein-coupled receptor contributes to meningococcal species selectivity, since Neu5Ac is only abundant in humans due to the loss of CMAH, the enzyme converting Neu5Ac into N-glycolyl-neuraminic acid in other mammals. It represents an additional mechanism of evolutionary adaptation of a pathogen to its host.

scholarly journals Binding mode and free energy prediction of fisetin/β-cyclodextrin inclusion complexes

2014 ◽  
Vol 10 ◽  
pp. 2789-2799 ◽  
Author(s):  
Bodee Nutho ◽  
Wasinee Khuntawee ◽  
Chompoonut Rungnim ◽  
Piamsook Pongsawasdi ◽  
Peter Wolschann ◽  
...  
Keyword(s):  
Free Energy ◽  
Molecular Docking ◽  
Phenyl Ring ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Binding Mode ◽  
Free Energy Calculations ◽  
Energy Prediction ◽  
Theoretical Approaches ◽  
Preferential Binding

In the present study, our aim is to investigate the preferential binding mode and encapsulation of the flavonoid fisetin in the nano-pore of β-cyclodextrin (β-CD) at the molecular level using various theoretical approaches: molecular docking, molecular dynamics (MD) simulations and binding free energy calculations. The molecular docking suggested four possible fisetin orientations in the cavity through its chromone or phenyl ring with two different geometries of fisetin due to the rotatable bond between the two rings. From the multiple MD results, the phenyl ring of fisetin favours its inclusion into the β-CD cavity, whilst less binding or even unbinding preference was observed in the complexes where the larger chromone ring is located in the cavity. All MM- and QM-PBSA/GBSA free energy predictions supported the more stable fisetin/β-CD complex of the bound phenyl ring. Van der Waals interaction is the key force in forming the complexes. In addition, the quantum mechanics calculations with M06-2X/6-31G(d,p) clearly showed that both solvation effect and BSSE correction cannot be neglected for the energy determination of the chosen system.

scholarly journals Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike Receptor-Binding Domain Bound with ACE2 COVID19 Target Proteins: A Virtual Drug Repurposing Study

2020 ◽  
Author(s):  
Serdar Durdagi ◽  
Busecan Aksoydan ◽  
Berna Dogan ◽  
Kader Sahin ◽  
Aida Shahraki ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Binding Energies ◽  
Protein Domain ◽  
Spike Protein ◽  
Docking Simulations ◽  
Main Protease

In this virtual drug repurposing study, we used 7922 FDA approved drugs and compounds in clinical investigation from NPC database. Both apo and holo forms of SARS-CoV-2 Main Protease as well as Spike Protein/ACE2 were used for virtual screening. Initially, docking was performed for these compounds at target binding sites. The compounds were then sorted according to their docking scores which represent binding energies. The first 100 compounds from each docking simulations were initially subjected to short (10 ns) MD simulations (in total 300 ligand-bound complexes), and average binding energies during MD simulations were calculated using the MM/GBSA method. Then, the selected promising hit compounds based on average MM/GBSA scores were used in long (100-ns and 500-ns) MD simulations. In total around 15 µs MD simulations were performed in this study. Both docking and MD simulations binding free energy calculations showed that holo form of the target protein is more appropriate choice for virtual drug screening studies. These numerical calculations have shown that the following 8 compounds can be considered as SARS-CoV-2 Main Protease inhibitors: Pimelautide, Rotigaptide, Telinavir, Ritonavir, Pinokalant, Terlakiren, Cefotiam and Cefpiramide. In addition, following 5 compounds were identified as potential SARS-CoV-2 ACE-2/Spike protein domain inhibitors: Denopamine, Bometolol, Naminterol, Rotigaptide and Benzquercin. These compounds can be clinically tested and if the simulation results validated, they may be considered to be used as treatment for COVID-19.

scholarly journals Screening of Clinically Approved and Investigation Drugs as Potential Inhibitors of SARS-CoV-2 Main Protease and Spike Receptor-Binding Domain Bound with ACE2 COVID19 Target Proteins: A Virtual Drug Repurposing Study

2020 ◽  
Author(s):  
Serdar Durdagi ◽  
Busecan Aksoydan ◽  
Berna Dogan ◽  
Kader Sahin ◽  
Aida Shahraki ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Free Energy Calculations ◽  
Binding Energies ◽  
Protein Domain ◽  
Spike Protein ◽  
Docking Simulations ◽  
Main Protease

In this virtual drug repurposing study, we used 7922 FDA approved drugs and compounds in clinical investigation from NPC database. Both apo and holo forms of SARS-CoV-2 Main Protease as well as Spike Protein/ACE2 were used for virtual screening. Initially, docking was performed for these compounds at target binding sites. The compounds were then sorted according to their docking scores which represent binding energies. The first 100 compounds from each docking simulations were initially subjected to short (10 ns) MD simulations (in total 300 ligand-bound complexes), and average binding energies during MD simulations were calculated using the MM/GBSA method. Then, the selected promising hit compounds based on average MM/GBSA scores were used in long (100-ns and 500-ns) MD simulations. In total around 15 µs MD simulations were performed in this study. Both docking and MD simulations binding free energy calculations showed that holo form of the target protein is more appropriate choice for virtual drug screening studies. These numerical calculations have shown that the following 8 compounds can be considered as SARS-CoV-2 Main Protease inhibitors: Pimelautide, Rotigaptide, Telinavir, Ritonavir, Pinokalant, Terlakiren, Cefotiam and Cefpiramide. In addition, following 5 compounds were identified as potential SARS-CoV-2 ACE-2/Spike protein domain inhibitors: Denopamine, Bometolol, Naminterol, Rotigaptide and Benzquercin. These compounds can be clinically tested and if the simulation results validated, they may be considered to be used as treatment for COVID-19.

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