scholarly journals Quantifying the adhesive strength between the SARS-CoV-2 S-proteins and human receptor and its effect in therapeutics

2020 ◽  
Author(s):  
Mauricio Ponga de la Torre
Keyword(s):  
Binding Energy ◽  
Binding Affinity ◽  
Adhesive Strength ◽  
Computational Design ◽  
Md Simulations ◽  
Adhesive Force ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Target Binding ◽  
S Proteins

Abstract The binding affinity and adhesive strength between the spike (S) glycoproteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the human angiotensin-converting enzyme 2 (ACE2) receptor is computed using molecular dynamics (MD) simulations. The calculations indicate that the binding affinity is e RS = 12.6 ± 1 kCal∙mol-1 with a maximum adhesive force of ~102 pN. Our analysis suggests that only 27 (13 in S-protein, 14 in ACE2) residues are active during the initial fusion process between the S-protein and ACE2 receptor. With these insights, we investigated the effect of possible therapeutics in the size and wrapping time of virus particles by reducing the binding energy. Our analysis indicates that this energy has to be reduced significantly, around 50% or more, to block SARS-CoV-2 particles with radius in the order of R≤60 nm. Our study provides concise target residues and target binding energy reduction between S-proteins and receptors for the development of new therapeutics treatments for COVID-19 guided by computational design.

scholarly journals Quantifying the adhesive strength between the SARS-CoV-2 S-proteins and human receptor and its effect in therapeutics

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mauricio Ponga
Keyword(s):  
Binding Energy ◽  
Binding Affinity ◽  
Adhesive Strength ◽  
Computational Design ◽  
Md Simulations ◽  
Adhesive Force ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Target Binding ◽  
S Proteins

Abstract The binding affinity and adhesive strength between the spike (S) glycoproteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the human angiotensin-converting enzyme 2 (ACE2) receptor is computed using molecular dynamics (MD) simulations. The calculations indicate that the binding affinity is $$e_{RS}= 12.6 \pm 1$$ e RS = 12.6 ± 1 $$\hbox {kCal}{\cdot }\hbox {mol}^{-1}$$ kCal · mol - 1 with a maximum adhesive force of $$\sim 102$$ ∼ 102 pN. Our analysis suggests that only 27 (13 in S-protein, 14 in ACE2) residues are active during the initial fusion process between the S-protein and ACE2 receptor. With these insights, we investigated the effect of possible therapeutics in the size and wrapping time of virus particles by reducing the binding energy. Our analysis indicates that this energy has to be reduced significantly, around 50% or more, to block SARS-CoV-2 particles with radius in the order of $$R\le 60$$ R ≤ 60 nm. Our study provides concise target residues and target binding energy reduction between S-proteins and receptors for the development of new therapeutics treatments for COVID-19 guided by computational design.

scholarly journals Quantifying the adhesive strength between the SARS-CoV-2 S-proteins and human receptor and its effect in therapeutics

2020 ◽  
Author(s):  
Mauricio Ponga de la Torre
Keyword(s):  
Binding Energy ◽  
Binding Affinity ◽  
Adhesive Strength ◽  
Computational Design ◽  
Md Simulations ◽  
Adhesive Force ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Target Binding ◽  
S Proteins

Abstract The binding affinity and adhesive strength between the spike (S) glycoproteins of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and the human angiotensin-converting enzyme 2 (ACE2) receptor is computed using molecular dynamics (MD) simulations. The calculations indicate that the binding affinity is eRS= 12.6 +/- 1 kCal mol-1 with a maximum adhesive force of ~102 pN. Our analysis suggests that only 27 (13 in S-protein, 14 in ACE2) residues are active during the initial fusion process between the S-protein and ACE2 receptor. With these insights, we investigated the effect of possible therapeutics in the size and wrapping time of virus particles by reducing the binding energy. Our analysis indicates that this energy has to be reduced significantly, around 50\% or more, to block SARS-CoV-2 particles with radius in the order of R < 60 nm. Our study provides concise target residues and target binding energy reduction between S-proteins and receptors for the development of new therapeutics treatments for COVID-19 guided by computational design.

scholarly journals S494 O-glycosylation site on the SARS-COV-2 RBD Affects the Virus Affinity to ACE2 and its Infectivity; A Molecular Dynamics Study

2020 ◽  
Author(s):  
Shadi Rahnama ◽  
Maryam Azimzadeh Irani ◽  
Mehriar Amininasab ◽  
Mohammad Reza Ejtehadi
Keyword(s):  
Molecular Dynamics ◽  
Md Simulations ◽  
Glycosylation Site ◽  
Virus Infectivity ◽  
Free Energies ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Host Interaction ◽  
Binding Free Energies

AbstractSARS-COV-2 is a strain of Coronavirus family which caused the extensive pandemic of COVID-19, which is still going on. Several studies showed that the glycosylation of virus spike (S) protein and the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the host cell is critical for the virus infectivity. Molecular Dynamics (MD) simulations were used to explore the role of a novel mutated O-glycosylation site (D494S) on the Receptor Binding Domain (RBD) of S protein. This site was suggested as a key mediator of virus-host interaction. We showed that the decoration of S494 with elongated O-glycans results in stabilized interactions on the direct RBD-ACE2 interface with more favorable binding free energies for longer oligosaccharides. Hence, this crucial factor must be taken into account for any further inhibitory approaches towards RBD-ACE2 interaction.

scholarly journals Impact of the Position of the Chemically Modified 5-Furyl-2′-Deoxyuridine Nucleoside on the Thrombin DNA Aptamer–Protein Complex: Structural Insights into Aptamer Response from MD Simulations

Molecules ◽  
2019 ◽  
Vol 24 (16) ◽  
pp. 2908 ◽  
Author(s):  
Preethi Seelam Prabhakar ◽  
Richard A. Manderville ◽  
Stacey D. Wetmore
Keyword(s):  
Binding Affinity ◽  
Structural Changes ◽  
Experimental Studies ◽  
Local Environment ◽  
Md Simulations ◽  
Fine Tuning ◽  
Dna Aptamer ◽  
Solvent Exposure ◽  
Chemically Modified ◽  
Target Binding

Aptamers are functional nucleic acids that bind to a range of targets (small molecules, proteins or cells) with a high affinity and specificity. Chemically-modified aptamers are of interest because the incorporation of novel nucleobase components can enhance aptamer binding to target proteins, while fluorescent base analogues permit the design of functional aptasensors that signal target binding. However, since optimally modified nucleoside designs have yet to be identified, information about how to fine tune aptamer stability and target binding affinity is required. The present work uses molecular dynamics (MD) simulations to investigate modifications to the prototypical thrombin-binding aptamer (TBA), which is a 15-mer DNA sequence that folds into a G-quadruplex structure connected by two TT loops and one TGT loop. Specifically, we modeled a previously synthesized thymine (T) analog, namely 5-furyl-2′-deoxyuridine (5FurU), into each of the six aptamer locations occupied by a thymine base in the TT or TGT loops of unbound and thrombin bound TBA. This modification and aptamer combination were chosen as a proof-of-principle because previous experimental studies have shown that TBA displays emissive sensitivity to target binding based on the local environment polarity at different 5FurU modification sites. Our simulations reveal that the chemically-modified base imparts noticeable structural changes to the aptamer without affecting the global conformation. Depending on the modification site, 5FurU performance is altered due to changes in the local environment, including the modification site structural dynamics, degree of solvent exposure, stacking with neighboring bases, and interactions with thrombin. Most importantly, these changes directly correlate with the experimentally-observed differences in the stability, binding affinity and emissive response of the modified aptamers. Therefore, the computational protocols implemented in the present work can be used in subsequent studies in a predictive way to aid the fine tuning of aptamer target recognition for use as biosensors (aptasensors) and/or therapeutics.

scholarly journals In silico Investigation on the Inhibiting Role of Nicotine/Caffeine by Blocking the S Protein of SARS-CoV-2 Versus ACE2 Receptor

2020 ◽  
Vol 8 (10) ◽  
pp. 1600 ◽  
Author(s):  
Saeedeh Mohammadi ◽  
Mohammad Heidarizadeh ◽  
Mehrnaz Entesari ◽  
Ayoub Esmailpour ◽  
Mohammad Esmailpour ◽  
...  
Keyword(s):  
In Silico ◽  
Active Sites ◽  
Md Simulations ◽  
Antiviral Drugs ◽  
Molar Ratio ◽  
Converting Enzyme ◽  
S Protein ◽  
Angiotensin Converting Enzyme 2 ◽  
Human Receptor

In this paper, we studied the in silico interaction of angiotensin-converting enzyme 2 (ACE2) human receptor with two bioactive compounds, i.e., nicotine and caffeine, via molecular dynamic (MD) simulations. The simulations reveal the efficient blocking of ACE2 by caffeine and nicotine in the exposure to the spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We have selected the two most important active sites of ACE2-S protein, i.e., 6LZG and 6VW1, which are critically responsible in the interaction of S protein to the receptor and thus, we investigated their interaction with nicotine and caffeine through MD simulations. Caffeine and nicotine are interesting structures for interactions because of their similar structure to the candidate antiviral drugs. Our results reveal that caffeine or nicotine in a specific molar ratio to 6LZG shows a very strong interaction and indicate that caffeine is more efficient in the interaction with 6LZG and further blocking of this site against S protein binding. Further, we investigated the interaction of ACE2 receptor- S protein with nicotine or caffeine when mixed with candidate or approved antiviral drugs for SARS-CoV-2 therapy. Our MD simulations suggest that the combination of caffeine with ribavirin shows a stronger interaction with 6VW1, while in case of favipiravir+nicotine, 6LZG shows potent efficacy of these interaction, proposing the potent efficacy of these combinations for blocking ACE2 receptor against SARS-CoV-2.

scholarly journals S494 O-glycosylation site on the SARS-CoV-2 RBD affects the virus affinity to ACE2 and its infectivity; a molecular dynamics study

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shadi Rahnama ◽  
Maryam Azimzadeh Irani ◽  
Mehriar Amininasab ◽  
Mohammad Reza Ejtehadi
Keyword(s):  
Molecular Dynamics ◽  
Binding Affinity ◽  
Binding Free Energy ◽  
Md Simulations ◽  
Glycosylation Site ◽  
Virus Infectivity ◽  
S Protein ◽  
Host Interaction ◽  
Binding Interface ◽  
Direct Binding

AbstractSARS-CoV-2 is a strain of Coronavirus family that caused the ongoing pandemic of COVID-19. Several studies showed that the glycosylation of virus spike (S) protein and the Angiotensin-Converting Enzyme 2 (ACE2) receptor on the host cell is critical for the virus infectivity. Molecular Dynamics (MD) simulations were used to explore the role of a novel mutated O-glycosylation site (D494S) on the Receptor Binding Domain (RBD) of S protein. This site was suggested as a key mediator of virus-host interaction. By exploring the dynamics of three O-glycosylated models and the control systems of unglcosylated S4944 and S494D complexes, it was shown that the decoration of S494 with elongated O-glycans results in stabilized interactions on the direct RBD-ACE2. Calculation of the distances between RBD and two major H1, H2 helices of ACE2 and the interacting pairs of amino acids in the interface showed that the elongated O-glycan maintains these interactions by forming several polar contacts with the neighbouring residues while it would not interfere in the direct binding interface. Relative binding free energy of RBD-ACE2 is also more favorable in the O-glycosylated models with longer glycans. The increase of RBD binding affinity to ACE2 depends on the size of attached O-glycan. By increasing the size of O-glycan, the RBD-ACE2 binding affinity will increase. Hence, this crucial factor must be taken into account for any further inhibitory approaches towards RBD-ACE2 interaction.

Quantitative structure-activity relationship model, molecular docking simulation and computational design of some novel compounds against DNA gyrase receptor.

2020 ◽  
Vol 16 ◽  
Author(s):  
Shola Elijah Adeniji
Keyword(s):  
Biological Activity ◽  
Molecular Docking ◽  
Binding Energy ◽  
Biological Activities ◽  
Docking Simulation ◽  
Dna Gyrase ◽  
Computational Design ◽  
Multi Drug Resistance ◽  
Drug Candidate ◽  
Standard Drug

Introduction: Mycobacterium tuberculosis has instigated a serious challenge toward the effective treatment of tuberculosis. The reoccurrence of the resistant strains of the disease to accessible drugs/medications has mandate for the development of more effective anti-tubercular agents with efficient activities. Time expended and costs in discovering and synthesizing new hypothetical drugs with improved biological activity have been a major challenge toward the treatment of multi-drug resistance strain M. tuberculosis (TB). Meanwhile, to solve the problem stated, a new approach i.e. QSAR which establish connection between novel drugs with a better biological against M. tuberculosis is adopted. Methods: The anti-tubercular model established in this study to forecast the biological activities of some anti-tubercular compounds selected and to design new hypothetical drugs is subjective to the molecular descriptors; MATS7s, SM1_DzZ, SpMin4_Bhv, TDB3v and RDF70v. Ligand-receptor interactions between quinoline derivatives and the receptor (DNA gyrase) was carried out using molecular docking technique by employing the PyRx virtual screening software and discovery studio visualizer software. Furthermore, docking study indicates that compounds 20 of the derivatives with promising biological activity have the utmost binding energy of -17.79 kcal/mol. Results: Meanwhile, the interaction of the standard drug; isoniazid with the target enzyme was observed with the binding energy -14.6 kcal/mol which was significantly lesser than the binding energy of the ligand (compound 20).Therefore, compound 20 served as a template structure to designed compounds with more efficient activities. Among the compounds designed; compounds 20p was observed with better anti-tubercular activities with more prominent binding affinities of -24.3kcal/mol. Conclusion: The presumption of this research aid the medicinal chemists and pharmacist to design and synthesis a novel drug candidate against the tuberculosis. Moreover, in-vitro and in-vivo test could be carried out to validate the computational results.

scholarly journals Inhibition of MMP2-PEX by a novel ester of dihydroxy cinnamic and linoleic acid from the seagrass Cymodocea serrulata

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
V. S. Christina ◽  
R. Lakshmi Sundaram ◽  
V. Sivamurugan ◽  
D. Thirumal Kumar ◽  
C. D. Mohanapriya ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Ovarian Cancer Cell Line ◽  
Cancer Cell Line ◽  
Md Simulations ◽  
Cell Types ◽  
Structural Details ◽  
M Phase ◽  
Ft Ir ◽  
Target Binding ◽  
Cymodocea Serrulata

AbstractMatrix metalloproteinases (MMPs) are pivotal for cancer cell migration and metastasis which are generally over-expressed in such cell types. Many drugs targeting MMPs do so by binding to the conserved catalytic domains and thus exhibit poor selectivity due to domain-similarities with other proteases. We report herein the binding of a novel compound [3-(E-3,4-dihydroxycinnamaoyloxyl)-2-hydroxypropyl 9Z, 12Z-octadeca-9, 12-dienoate; Mol. wt: 516.67 Da], (C1), isolated from a seagrass, Cymodocea serrulata to the unconserved hemopexin-like (PEX) domain of MMP2 (− 9.258 kcal/mol). MD simulations for 25 ns, suggest stable ligand-target binding. In addition, C1 killed an ovarian cancer cell line, PA1 at IC50: 5.8 μM (lesser than Doxorubicin: 8.6 µM) and formed micronuclei, apoptotic bodies and nucleoplasmic bridges whilst causing DNA laddering, S and G2/M phase dual arrests and MMP disturbance, suggesting intrinsic apoptosis. The molecule increased mRNA transcripts of BAX and BAD and down-regulated cell survival genes, Bcl-xL, Bcl-2, MMP2 and MMP9. The chemical and structural details of C1 were deduced through FT-IR, GC–MS, ESI–MS, 1H and 13C NMR [both 1D and 2D] spectra.

From the discovery to molecular understanding of cellular iron-sulfur protein biogenesis

2020 ◽  
Vol 401 (6-7) ◽  
pp. 855-876 ◽  
Author(s):  
Roland Lill
Keyword(s):  
De Novo ◽  
Current Knowledge ◽  
Protein Stabilization ◽  
S Protein ◽  
Cellular Iron ◽  
Iron Sulfur ◽  
Protein Biogenesis ◽  
Sulfur Protein ◽  
Initial Discovery ◽  
S Proteins

AbstractProtein cofactors often are the business ends of proteins, and are either synthesized inside cells or are taken up from the nutrition. A cofactor that strictly needs to be synthesized by cells is the iron-sulfur (Fe/S) cluster. This evolutionary ancient compound performs numerous biochemical functions including electron transfer, catalysis, sulfur mobilization, regulation and protein stabilization. Since the discovery of eukaryotic Fe/S protein biogenesis two decades ago, more than 30 biogenesis factors have been identified in mitochondria and cytosol. They support the synthesis, trafficking and target-specific insertion of Fe/S clusters. In this review, I first summarize what led to the initial discovery of Fe/S protein biogenesis in yeast. I then discuss the function and localization of Fe/S proteins in (non-green) eukaryotes. The major part of the review provides a detailed synopsis of the three major steps of mitochondrial Fe/S protein biogenesis, i.e. the de novo synthesis of a [2Fe-2S] cluster on a scaffold protein, the Hsp70 chaperone-mediated transfer of the cluster and integration into [2Fe-2S] recipient apoproteins, and the reductive fusion of [2Fe-2S] to [4Fe-4S] clusters and their subsequent assembly into target apoproteins. Finally, I summarize the current knowledge of the mechanisms underlying the maturation of cytosolic and nuclear Fe/S proteins.

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