scholarly journals A Case for Montelukast in COVID-19: "The use of Computational Docking to estimate the effects of Montelukast on potential viral main protease catalytic site"

2020 ◽  
Author(s):  
Salman Mansoor ◽  
Shoab Saadat ◽  
Aitzaz Amin ◽  
Imran Ali ◽  
Muhammad Tauseef Ghaffar ◽  
...  
Keyword(s):  
Hydrophobic Interactions ◽  
Data Bank ◽  
Catalytic Site ◽  
Amino Acid Residues ◽  
Direct Effects ◽  
Computational Docking ◽  
Main Protease ◽  
A Chain ◽  
Homology Models

Abstract This article explores the possible role of Montelukast in management of SARS-CoV-2 infection after reviewing the available literature and further uses computational docking to estimate the effects of Montelukast on the main protease inhibitor site of SARS-CoV-2.Methodology: In this study, we used molecular docking to estimate the direct effects of Montelukast on the main protease (Mpro) inhibitor site of the SARS-CoV-2. While other studies have been performed on the homology models, we obtained the Mpro crystalized structure, A-chain (304 amino acid residues) from protein data bank (PDB code 5REK) for this analysisResults:The best docked Montelukast conformer had a mfscore of -71.68 and was seen to be making multiple hydrogen bonds with the neighbouring residues (T24, T24, T26, S46) with the closest bond with T24 (Distance= 1.71 angstrom). Important finding was its hydrogen bond with H41 and hydrophobic interactions with C145 as these residues for important members of the active catalytics site.Conclusion:The computational model which was used against the crystalized Mpro structure suggested a possible inhibitory role of Montelukast in binding to the Mpro catalytic site which may modulate and inhibit the viral replication.

scholarly journals The Potential Role of 6-gingerol and 6-shogaol as ACE Inhibitors in Silico Study

2020 ◽  
Vol 8 (2) ◽  
pp. 210
Author(s):  
Yohanes Bare ◽  
Maria Helvina ◽  
Gabriella Chandrakirana Krisnamurti ◽  
Mansur S
Keyword(s):  
Amino Acid ◽  
Angiotensin Converting Enzyme ◽  
Binding Site ◽  
Potential Role ◽  
Enzyme Inhibitor ◽  
Renin Angiotensin System ◽  
Data Bank ◽  
Amino Acid Residues ◽  
Converting Enzyme

Hypertension has become the third highest cause of death in Indonesia. The condition is correlated with angiotensin-converting enzyme (ACE), and possibly managed with the use of drugs. In addition, some natural compounds, including 6-shogaol and 6-gingerol from ginger, are used to decrease blood pressure. However, the mechanism and binding site of these compounds to ACE protein is currently unclear. This study, therefore, aims to investigate the potential role of these compounds as an angiotensin-converting enzyme inhibitor. The ACE protein was downloaded from Protein Data Bank (PDB) database with the ID: 3bkk, while the 6-shogaol (CID: 5281794) and 6-gingerol (CID: 44559528) ligands were obtained from the PubChem database. Meanwhile, molecular docking was established using HEX 8.0.0 software. The analysis examined the amino acid residues and the bonds formed from these interactions. According to the results, fourteen amino acid residues were formed by the interaction between 6-shogaol and ACE, while the interaction between 6-gingerol and ACE formed eight amino acids. Also, thirteen amino acid residues in the novelty binding site of ACE were discovered to be blocked by the ligands from ginger. Therefore, the compounds have potential roles as inhibitors, and this possibly helps to prevent regulation of the renin-angiotensin system. These interactions also formed hydrogen bonds, as well as electrostatic, unfavorable, and hydrophobic sites, making the binding stronger than others. 

scholarly journals Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 Main Protease complexes reveal the role of a lateral pocket in enhancing the ligand affinity

2020 ◽  
Author(s):  
Ying Li Weng ◽  
Shiv Rakesh Naik ◽  
Nadia Dingelstad ◽  
Subha Kalyaanamoorthy ◽  
Aravindhan Ganesan
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Conformational Dynamics ◽  
Data Bank ◽  
Reversible Inhibitor ◽  
Dynamic Interactions ◽  
Ongoing Research ◽  
Main Protease ◽  
Novel Coronavirus

AbstractThe 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and a number of countries are already in the middle of the second wave of infection. There is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (Mpro) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 Mpro that resulted in hundreds of X-ray crystal structures of ligand bound Mpro complexes in the protein data bank (PDB) that describe structural details of different chemotypes of fragments binding within different sites in Mpro. In this work, we perform rigorous molecular dynamics (MD) simulation of 62 reversible ligand-Mpro complexes in the PDB to gain mechanistic insights about their interactions at atomic level. Using a total of ~2.25 μs long MD trajectories, we identified and characterized different pockets and their conformational dynamics in the apo Mpro structure. Later, using the published PDB structures, we analyzed the dynamic interactions and binding affinity of small ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets in Mpro. Our analyses unraveled the role of a lateral pocket in the catalytic site in Mpro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in this lateral pocket towards ligand binding and affinity against Mpro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and Mpro dimerization in the ligand association with the target. Thus, comprehensive molecular level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 Mpro.

scholarly journals Electrostatic compared with hydrophobic interactions between bovine serum amine oxidase and its substrates

2003 ◽  
Vol 371 (2) ◽  
pp. 549-556 ◽  
Author(s):  
Maria Luisa DI PAOLO ◽  
Roberto STEVANATO ◽  
Alessandra CORAZZA ◽  
Fabio VIANELLO ◽  
Lorenzo LUNELLI ◽  
...  
Keyword(s):  
Active Site ◽  
Bovine Serum ◽  
Hydrophobic Interactions ◽  
Amine Oxidase ◽  
Amino Acid Residues ◽  
Deprotonated Form ◽  
Steady State Kinetic ◽  
Wide Range ◽  
Order Of Magnitude

A steady-state kinetic study of bovine serum amine oxidase activity was performed, over a wide range of pH values (5.4–10.2) and ionic strength (10–200mM), using various (physiological and analogue) substrates as specific probes of the active-site binding region. Relatively small changes in kcat values (approx. one order of magnitude) accompanied by marked changes in Km and kcat/Km values (approx. six orders of magnitude) were observed. This behaviour was correlated with the presence of positively charged groups or apolar chains in the substrates. In particular, it was found that the docking of the physiological polyamines, i.e. spermidine and spermine, appears to be modulated by three amino acid residues of the active site, which we have named L-H+, G-H+ and IH+, characterized by pKa values of 6.2±0.2 [Di Paolo, Scarpa, Corazza, Stevanato and Rigo (2002) Biophys. J. 83, 2231–2239], 8.2±0.3 and 7.8±0.4 respectively. The electrostatic interaction between the protonated substrates and the enzyme containing the residues L-H+, G-H+ and IH+ in the deprotonated form, the on/off role of the IH+ residue and the role of hydrophobic interactions with substrates characterized by apolar chains are discussed.

scholarly journals Unusual zwitterionic catalytic site of SARS–CoV-2 main protease revealed by neutron crystallography

2020 ◽  
Vol 295 (50) ◽  
pp. 17365-17373 ◽  
Author(s):  
Daniel W. Kneller ◽  
Gwyndalyn Phillips ◽  
Kevin L. Weiss ◽  
Swati Pant ◽  
Qiu Zhang ◽  
...  
Keyword(s):  
Active Site ◽  
Direct Determination ◽  
Catalytic Site ◽  
Amino Acid Residues ◽  
Critical Question ◽  
Main Protease ◽  
Neutron Structure ◽  
Active Site Cavity ◽  
Ionizable Residues ◽  
Essential Enzyme

The main protease (3CL Mpro) from SARS–CoV-2, the etiological agent of COVID-19, is an essential enzyme for viral replication. 3CL Mpro possesses an unusual catalytic dyad composed of Cys145 and His41 residues. A critical question in the field has been what the protonation states of the ionizable residues in the substrate-binding active-site cavity are; resolving this point would help understand the catalytic details of the enzyme and inform rational drug development against this pernicious virus. Here, we present the room-temperature neutron structure of 3CL Mpro, which allowed direct determination of hydrogen atom positions and, hence, protonation states in the protease. We observe that the catalytic site natively adopts a zwitterionic reactive form in which Cys145 is in the negatively charged thiolate state and His41 is doubly protonated and positively charged, instead of the neutral unreactive state usually envisaged. The neutron structure also identified the protonation states, and thus electrical charges, of all other amino acid residues and revealed intricate hydrogen-bonding networks in the active-site cavity and at the dimer interface. The fine atomic details present in this structure were made possible by the unique scattering properties of the neutron, which is an ideal probe for locating hydrogen positions and experimentally determining protonation states at near-physiological temperature. Our observations provide critical information for structure-assisted and computational drug design, allowing precise tailoring of inhibitors to the enzyme's electrostatic environment.

scholarly journals The Role of Amino Acid Residues Located at the Catalytic Site in the Rotation of Enterococcus Hirae V1-ATPase

2015 ◽  
Vol 108 (2) ◽  
pp. 162a
Author(s):  
Yoshihiro Minagawa ◽  
Ueno Hiroshi ◽  
Mayu Hara ◽  
Hiroyuki Noji ◽  
Takeshi Murata ◽  
...  
Keyword(s):  
Amino Acid ◽  
Catalytic Site ◽  
Amino Acid Residues ◽  
Enterococcus Hirae ◽  
V1 Atpase

scholarly journals Molecular dynamics and in silico mutagenesis on the reversible inhibitor-bound SARS-CoV-2 main protease complexes reveal the role of lateral pocket in enhancing the ligand affinity

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ying Li Weng ◽  
Shiv Rakesh Naik ◽  
Nadia Dingelstad ◽  
Miguel R. Lugo ◽  
Subha Kalyaanamoorthy ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Ligand Binding ◽  
Data Bank ◽  
Reversible Inhibitor ◽  
Dynamic Interactions ◽  
Ongoing Research ◽  
Drug Candidates ◽  
Main Protease ◽  
Novel Coronavirus

AbstractThe 2019 novel coronavirus pandemic caused by SARS-CoV-2 remains a serious health threat to humans and there is an urgent need to develop therapeutics against this deadly virus. Recent scientific evidences have suggested that the main protease (Mpro) enzyme in SARS-CoV-2 can be an ideal drug target due to its crucial role in the viral replication and transcription processes. Therefore, there are ongoing research efforts to identify drug candidates against SARS-CoV-2 Mpro that resulted in hundreds of X-ray crystal structures of ligand-bound Mpro complexes in the Protein Data Bank (PDB) describing the interactions of different fragment chemotypes within different sites of the Mpro. In this work, we performed rigorous molecular dynamics (MD) simulation of 62 reversible ligand–Mpro complexes in the PDB to gain mechanistic insights about their interactions at the atomic level. Using a total of over 3 µs long MD trajectories, we characterized different pockets in the apo Mpro structure, and analyzed the dynamic interactions and binding affinity of ligands within those pockets. Our results identified the key residues that stabilize the ligands in the catalytic sites and other pockets of Mpro. Our analyses unraveled the role of a lateral pocket in the catalytic site in Mpro that is critical for enhancing the ligand binding to the enzyme. We also highlighted the important contribution from HIS163 in the lateral pocket towards ligand binding and affinity against Mpro through computational mutation analyses. Further, we revealed the effects of explicit water molecules and Mpro dimerization in the ligand association with the target. Thus, comprehensive molecular-level insights gained from this work can be useful to identify or design potent small molecule inhibitors against SARS-CoV-2 Mpro.

Effect of human galanin on the response of circulating catecholamines to hypoglycemia in man

1995 ◽  
Vol 133 (6) ◽  
pp. 723-728 ◽  
Author(s):  
Ettore C degli Uberti ◽  
Maria R Ambrosio ◽  
Marta Bondanelli ◽  
Giorgio Transforini ◽  
Alberto Valentini ◽  
...  
Keyword(s):  
Heart Rate ◽  
Healthy Subjects ◽  
Sympathetic Nerve Activity ◽  
Heart Rate Response ◽  
Statistical Significance ◽  
Inhibitory Effect ◽  
Amino Acid Residues ◽  
Nerve Activity ◽  
Receptor Stimulation

degli Uberti EC, Ambrosio MR, Bondanelli M, Trasforini G, Valentini A, Rossi R, Margutti A, Campo M. Effect of human galanin on the response of circulating catecholamines to hypoglycemia in man. Eur J Endocrinol 1995;133:723–8. ISSN 0804–4643 Human galanin (hGAL) is a neuropeptide with 30 amino acid residues that has been found in the peripheral and central nervous system, where it often co-exists with catecholamines. In order to clarify the possible role of hGAL in the regulation of sympathoadrenomedullary function, the effect of a 60 min infusion of hGAL (80 pmol·kg−1 · min−1) on plasma epinephrine and norepinephrine responses to insulin-induced hypoglycemia in nine healthy subjects was investigated. Human GAL administration significantly reduced both the release of basal norepinephrine and the response to insulin-induced hypoglycemia, whereas it attenuated the epinephrine response by 26%, with the hGAL-induced decrease in epinephrine release failing to achieve statistical significance. Human GAL significantly increased the heart rate in resting conditions and clearly exaggerated the heart rate response to insulin-induced hypoglycemia, whereas it had no effect on the blood pressure. We conclude that GAL receptor stimulation exerts an inhibitory effect on basal and insulin-induced hypoglycemia-stimulated release of norepinephrine. These findings provide further evidence that GAL may modulate sympathetic nerve activity in man but that it does not play an important role in the regulation of adrenal medullary function. Ettore C degli Uberti, Chair of Endocrinology, University of Ferrara, Via Savonarola 9, I-44100 Ferrara, Italy

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