Identification of Potential SARS-CoV-2 Main Protease and Spike Protein Inhibitors from the Genus Aloe: An In Silico Study for Drug Development

Molecules, Journal Year: 2021, Volume and Issue: 26(6), P. 1767 - 1767

Published: March 21, 2021

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) disease is a global rapidly spreading virus showing very high rates of complications and mortality. Till now, there no effective specific treatment for the disease. Aloe rich source isolated phytoconstituents that have an enormous range biological activities. Since are available experimental techniques to examine these compounds antiviral activity against SARS-CoV-2, we employed in silico approach involving molecular docking, dynamics simulation, binding free energy calculation using SARS-CoV-2 essential proteins as main protease spike protein identify lead from may help novel drug discovery. Results retrieved docking simulation suggested number promising inhibitors Aloe. Root mean square deviation (RMSD) root fluctuation (RMSF) calculations indicated 132, 134, 159 were best scoring protease, while 115, 120, 131 ones glycoprotein. Compounds 120 able achieve significant stability energies during simulation. In addition, highest investigated their pharmacokinetic properties drug-likeness. The active development SARS-CoV-2.

Language: Английский

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Exploring the Role of Glycans in the Interaction of SARS-CoV-2 RBD and Human Receptor ACE2

Viruses, Journal Year: 2021, Volume and Issue: 13(5), P. 927 - 927

Published: May 17, 2021

COVID-19 is a highly infectious respiratory disease caused by the novel coronavirus SARS-CoV-2. It has become global pandemic and its frequent mutations may pose new challenges for vaccine design. During viral infection, Spike RBD of SARS-CoV-2 binds human host cell receptor ACE2, enabling virus to enter cell. Both ACE2 are densely glycosylated, it unclear how distinctive glycan types modulate interaction ACE2. Detailed understanding these determinants key development therapeutic strategies. To this end, we perform extensive all-atom simulations (i) RBD-ACE2 complex without glycans, (ii) with oligomannose MAN9 glycans in (iii) FA2 These identify residues at interface that form contacts higher probabilities, thus providing quantitative evaluation complements recent structural studies. Notably, find contact signature not altered presence different glycoforms, suggesting robust. Applying our simulated results, illustrate recently prevalent N501Y mutation alter specific interactions facilitate virus-host binding. Furthermore, reveal on Asn90 can play distinct role binding unbinding RBD. Finally, an energetics analysis shows decrease affinity, while lead enhanced complex. Together, results provide more comprehensive picture detailed interplay between receptor, which much needed discovery effective treatments aim modulating physical-chemical properties virus.

Language: Английский

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SARS-CoV-2 Variants, RBD Mutations, Binding Affinity, and Antibody Escape

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(22), P. 12114 - 12114

Published: Nov. 9, 2021

Since 2020, the receptor-binding domain (RBD) of spike protein novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been constantly mutating, producing most notable missense mutations in context “variants concern”, probably response to vaccine-driven alteration immune profiles human population. The Delta variant, particular, become prevalent variant epidemic, and it is spreading countries with highest vaccination rates, causing world face risk a new wave contagion. Understanding physical mechanism responsible for mutation-induced changes RBD’s binding affinity, its transmissibility, capacity escape vaccine-induced immunity “urgent challenge” development preventive measures, vaccines, therapeutic antibodies against disease 2019 (COVID-19) pandemic. In this study, entropy–enthalpy compensation Gibbs free energy change were used analyze impact RBD on affinity SARS-CoV-2 variants receptor angiotensin converting enzyme (ACE2) existing antibodies. Through analysis, we found that have already covered almost all possible detrimental could result an increase mutation amino-acid position 498 can potentially enhance affinity. A calculation method energies protein–protein complexes proposed based rule. All known structures RBD–antibody RBD–ACE2 complex comply rule providing driving force behind spontaneous docking. variant-induced breakthrough infections vaccinated people attributed L452R mutation’s reduction many Mutations reversing hydrophobic or hydrophilic performance residues cause coronaviruses due geometric complementarity compensations between virus at sites.

Language: Английский

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Structural insights into the modulation of coronavirus spike tilting and infectivity by hinge glycans

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Nov. 7, 2023

Abstract Coronavirus spike glycoproteins presented on the virion surface mediate receptor binding, and membrane fusion during virus entry constitute primary target for vaccine drug development. How structure dynamics of full-length spikes incorporated in viral lipid envelope correlates with infectivity remains poorly understood. Here we present structures distributions native conformations vitrified human coronavirus NL63 (HCoV-NL63) virions without chemical fixation by cryogenic electron tomography (cryoET) subtomogram averaging, along site-specific glycan composition occupancy determined mass spectrometry. The higher oligomannose shield HCoV-NL63 than SARS-CoV-2 stronger immune evasion HCoV-NL63. Incorporation cryoET-derived into all-atom molecular dynamic simulations elucidate conformational landscape glycosylated, that reveals a role hinge glycans modulating bending. We show glycosylation at N1242 upper portion stalk is responsible extensive orientational freedom crown. Subsequent assays implicated involvement N1242-glyan entry. Our results suggest potential therapeutic site

Language: Английский

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Up State of the SARS-COV-2 Spike Homotrimer Favors an Increased Virulence for New Variants

Frontiers in Medical Technology, Journal Year: 2021, Volume and Issue: 3

Published: June 30, 2021

The COVID-19 pandemic has spread worldwide. However, as soon the first vaccines—the only scientifically verified and efficient therapeutic option thus far—were released, mutations combined into variants of SARS-CoV-2 that are more transmissible virulent emerged, raising doubts about their efficiency. This study aims to explain possible molecular mechanisms responsible for increased transmissibility rate hospitalizations related new variants. A combination theoretical methods was employed. Constant-pH Monte Carlo simulations were carried out quantify stability several spike trimeric structures at different conformational states free energy interactions between receptor-binding domain (RBD) angiotensin-converting enzyme II (ACE2) most worrying Electrostatic epitopes mapped using PROCEEDpKa method. These analyses showed virulence is likely be due improved S trimer in opened state, which virus can interact with cellular receptor, ACE2, rather than alterations complexation RBD-ACE2, since difference observed values small (although attractive general). Conversely, South African/Beta variant (B.1.351), compared wild type (wt), much stable state one or two RBDs up position closed three down favoring infection. Such results contribute understanding natural history disease indicate strategies developing molecules adjusting vaccine doses higher B-cell antibody production.

Language: Английский

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