scholarly journals Screening, simulation, and optimization design of small molecule inhibitors of the SARS-CoV-2 spike glycoprotein

PLoS ONE ◽  
2021 ◽  
Vol 16 (1) ◽  
pp. e0245975
Author(s):  
Chuancai Sun ◽  
Jian Zhang ◽  
Jiao Wei ◽  
Xiaoli Zheng ◽  
Xianyang Zhao ◽  
...  
Keyword(s):  
Small Molecule ◽  
Conformational Changes ◽  
Binding Sites ◽  
Optimization Design ◽  
Binding Energies ◽  
Host Cells ◽  
Spike Glycoprotein ◽  
S Protein ◽  
Simulation And Optimization ◽  
Interaction Sites

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) outbreak is a public health emergency of international concern. The spike glycoprotein (S protein) of SARS-CoV-2 is a key target of antiviral drugs. Focusing on the existing S protein structure, molecular docking was used in this study to calculate the binding energy and interaction sites between 14 antiviral molecules with different structures and the SARS-CoV-2 S protein, and the potential drug candidates targeting the SARS-CoV-2 S protein were analyzed. Tizoxanide, dolutegravir, bictegravir, and arbidol were found to have high binding energies, and they effectively bind key sites of the S1 and S2 subunits, inhibiting the virus by causing conformational changes in S1 and S2 during the fusion of the S protein with host cells. Based on the interactions among the drug molecules, the S protein and the amino acid environment around the binding sites, rational structure-based optimization was performed using the molecular connection method and bioisosterism strategy to obtain Ti-2, BD-2, and Ar-3, which have much stronger binding ability to the S protein than the original molecules. This study provides valuable clues for identifying S protein inhibitor binding sites and the mechanism of the anti-SARS-CoV-2 effect as well as useful inspiration and help for the discovery and optimization of small molecule S protein inhibitors.

scholarly journals Conformational Changes in the Spike Glycoprotein of Murine Coronavirus Are Induced at 37°C either by Soluble Murine CEACAM1 Receptors or by pH 8

2003 ◽  
Vol 77 (2) ◽  
pp. 830-840 ◽  
Author(s):  
Bruce D. Zelus ◽  
Jeanne H. Schickli ◽  
Dianna M. Blau ◽  
Susan R. Weiss ◽  
Kathryn V. Holmes
Keyword(s):  
Conformational Change ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Virus Neutralization ◽  
Virus Infectivity ◽  
Soluble Receptor ◽  
Spike Glycoprotein ◽  
S Protein ◽  
Neutral Ph ◽  
Murine Coronavirus

ABSTRACT The spike glycoprotein (S) of the murine coronavirus mouse hepatitis virus (MHV) binds to viral murine CEACAM receptor glycoproteins and causes membrane fusion. On virions, the 180-kDa S glycoprotein of the MHV-A59 strain can be cleaved by trypsin to form the 90-kDa N-terminal receptor-binding subunit (S1) and the 90-kDa membrane-anchored fusion subunit (S2). Incubation of virions with purified, soluble CEACAM1a receptor proteins at 37°C and pH 6.5 neutralizes virus infectivity (B. D. Zelus, D. R. Wessner, R. K. Williams, M. N. Pensiero, F. T. Phibbs, M. deSouza, G. S. Dveksler, and K. V. Holmes, J. Virol. 72:7237-7244, 1998). We used liposome flotation and protease sensitivity assays to investigate the mechanism of receptor-induced, temperature-dependent virus neutralization. After incubation with soluble receptor at 37°C and pH 6.5, virions became hydrophobic and bound to liposomes. Receptor binding induced a profound, apparently irreversible conformational change in S on the viral envelope that allowed S2, but not S1, to be degraded by trypsin at 4°C. Various murine CEACAM proteins triggered conformational changes in S on recombinant MHV strains expressing S glycoproteins of MHV-A59 or MHV-4 (MHV-JHM) with the same specificities as seen for virus neutralization and virus-receptor activities. Increased hydrophobicity of virions and conformational change in S2 of MHV-A59 could also be induced by incubating virions at pH 8 and 37°C, without soluble receptor. Surprisingly, the S protein of recombinant MHV-A59 virions with a mutation, H716D, that precluded cleavage between S1 and S2 could also be triggered to undergo a conformational change at 37°C by soluble receptor at neutral pH or by pH 8 alone. A novel 120-kDa subunit was formed following incubation of the receptor-triggered SA59H716D virions with trypsin at 4°C. The data show that unlike class 1 fusion glycoproteins of other enveloped viruses, the murine coronavirus S protein can be triggered to a membrane-binding conformation at 37°C either by soluble receptor at neutral pH or by alkaline pH alone, without requiring previous activation by cleavage between S1 and S2.

scholarly journals Virtual Screening of Plant-Derived Compounds Against SARS-CoV-2 Viral Proteins Using Computational Tools

2020 ◽  
Author(s):  
Maria Antonela Zigolo ◽  
Matías Rivero Goytia ◽  
Hugo Ramiro Poma ◽  
Verónica Rajal ◽  
Veronica Patricia Irazusta
Keyword(s):  
Hydrophobic Interactions ◽  
Viral Proteins ◽  
Natural Compounds ◽  
Docking Studies ◽  
Binding Energies ◽  
Host Cells ◽  
Computational Tools ◽  
S Protein ◽  
Synthetic Drugs ◽  
Main Protease

<p>The new SARS-CoV-2, responsible for the COVID-19 pandemic, has been threatening public health worldwide for half a year. The aim of this work was to evaluate compounds of natural origin, mainly from medicinal plants, as potential SARS-CoV-2 inhibitors through docking studies. The viral spike (S) glycoprotein and the main protease M<sup>pro</sup>, involved in the recognition of virus by host cells and in viral replication, respectively, were the main molecular targets in this study. </p> <p>The best energy binding values for S protein were, in kcal/mol: -19.22 for glycyrrhizin, -17.84 for gitoxin, -12.05 for dicumarol, -10.75 for diosgenin, and -8.12 for delphinidin. For M<sup>pro</sup> were, in kcal/mol: -9.36 for spirostan, -8.75 for <i>N</i>-(3-acetylglycyrrhetinoyl)-2-amino-propanol, -8.41 for α-amyrin, -8.35 for oleanane, -8.11 for taraxasterol, and -8.03 for glycyrrhetinic acid. In addition, the synthetic drugs umifenovir, chloroquine, and hydroxychloroquine were used as controls for S protein, while atazanavir and nelfinavir were used for M<sup>pro</sup>. Key hydrogen bonds and hydrophobic interactions between natural compounds and the respective viral proteins were identified, allowing us to explain the great affinity obtained in those compounds with the lowest binding energies. These results suggest that these natural compounds could potentially be useful as drugs to be experimentally evaluated against COVID-19. </p>

scholarly journals Two-Step Conformational Changes in a Coronavirus Envelope Glycoprotein Mediated by Receptor Binding and Proteolysis

2009 ◽  
Vol 83 (21) ◽  
pp. 11133-11141 ◽  
Author(s):  
Shutoku Matsuyama ◽  
Fumihiro Taguchi
Keyword(s):  
Cell Surface ◽  
Membrane Fusion ◽  
Receptor Binding ◽  
Conformational Changes ◽  
Hydrophobic Interactions ◽  
Sodium Dodecyl ◽  
Host Cells ◽  
Heptad Repeat ◽  
Soluble Form ◽  
S Protein

ABSTRACT The coronaviruses mouse hepatitis virus type 2 (MHV-2) and severe acute respiratory syndrome coronavirus (SARS-CoV) utilize proteases to enter host cells. Upon receptor binding, the spike (S) proteins of both viruses are activated for membrane fusion by proteases, such as trypsin, present in the environment, facilitating virus entry from the cell surface. In contrast, in the absence of extracellular proteases, these viruses can enter cells via an endosomal pathway and utilize endosomal cathepsins for S protein activation. We demonstrate that the MHV-2 S protein uses multistep conformational changes for membrane fusion. After interaction with a soluble form of the MHV receptor (CEACAM1a), the metastable form of S protein is converted to a stable trimer, as revealed by mildly denaturing sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Liposome-binding assays indicate that the receptor-bound virions are associated with the target membrane through hydrophobic interactions. The exposure of receptor-bound S protein to trypsin or cathepsin L (CPL) induces the formation of six-helix bundles (6HB), the final conformation. This trypsin- or CPL-mediated conversion to 6HB can be blocked by a heptad repeat peptide known to block the formation of 6HB. Although trypsin treatment enabled receptor-bound MHV-2 to enter from the cell surface, CPL failed to do so. Interestingly, consecutive treatment with CPL and then chlorpromazine enabled a portion of the virus to enter from cell surface. These results suggest that trypsin suffices for the induction of membrane fusion of receptor-primed S protein, but an additional unidentified cellular factor is required to trigger membrane fusion by CPL.

scholarly journals Structural basis of SARS-CoV-2 spike protein induced by ACE2

2020 ◽  
Author(s):  
Tomer Meirson ◽  
David Bomze ◽  
Gal Markel
Keyword(s):  
Conformational Changes ◽  
Viral Entry ◽  
Active Form ◽  
Intramolecular Interactions ◽  
Host Cells ◽  
Supplementary Information ◽  
Structural Basis ◽  
S Protein ◽  
Binding Interface ◽  
Recent Emergence

Abstract Motivation The recent emergence of the novel SARS-coronavirus 2 (SARS-CoV-2) and its international spread pose a global health emergency. The spike (S) glycoprotein binds ACE2 and promotes SARS-CoV-2 entry into host cells. The trimeric S protein binds the receptor using the receptor-binding domain (RBD) causing conformational changes in S protein that allow priming by host cell proteases. Unraveling the dynamic structural features used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal novel therapeutic targets. Using structures determined by X-ray crystallography and cryo-EM, we performed structural analysis and atomic comparisons of the different conformational states adopted by the SARS-CoV-2-RBD. Results Here, we determined the key structural components induced by the receptor and characterized their intramolecular interactions. We show that κ-helix (polyproline-II) is a predominant structure in the binding interface and in facilitating the conversion to the active form of the S protein. We demonstrate a series of conversions between switch-like κ-helix and β-strand, and conformational variations in a set of short α-helices which affect the hinge region. These conformational changes lead to an alternating pattern in conserved disulfide bond configurations positioned at the hinge, indicating a possible disulfide exchange, an important allosteric switch implicated in viral entry of various viruses, including HIV and murine coronavirus. The structural information presented herein enables to inspect and understand the important dynamic features of SARS-CoV-2-RBD and propose a novel potential therapeutic strategy to block viral entry. Overall, this study provides guidance for the design and optimization of structure-based intervention strategies that target SARS-CoV-2. Availability and implementation We have implemented the proposed methods in an R package freely available at https://github.com/Grantlab/bio3d. Supplementary information Supplementary data are available at Bioinformatics online.

Compatibility of the Ligand Binding Sites in the Spike Glycoprotein of COVID-19 with those in the Aminopeptidase and the Caveolins 1, 2 Proteins

2021 ◽  
pp. 4760-4766
Author(s):  
Ali Adel Dawood ◽  
Mahmood Abduljabar Altobje ◽  
Haitham Abdul-Malik Alnori
Keyword(s):  
Ligand Binding ◽  
Viral Entry ◽  
Binding Sites ◽  
In Silico Analysis ◽  
Cell Receptor ◽  
Spike Glycoprotein ◽  
Strong Response ◽  
Interaction Sites ◽  
Ligand Binding Sites ◽  
Interaction Domains

A novel severe viral pneumonia emerged in Wuhan city, China, in December 2019. The spike glycoprotein of the SARS-CoV-2 plays a crucial role in the viral entry to the host cell and eliciting a strong response for antibody-mediated neutralization in mice. Caveolins 1,2 are scaffolding proteins dovetailed as a co-stimulatory signal essential for T-cell receptor and activation. Aminopeptidase is a membrane protein acting as a receptor for human coronavirus within the S1 subunit of the spike glycoprotein. Vaccines for COVID-19 have become a priority for predisposition against the outbreak, so that our study aimed to find interaction sites between SP of SARS-CoV-2 and CAV1, CAV2, and AMPN. Methods: Amino acids motif search was employed to predict the possible CAV1, CAV2, and AMPN related interaction domains in the SARS-CoV-2 SP In silico analysis. Results: Interactions between proteins revealed 5 and16 residues. ZN ligand binding site is matched between AMPN and SARS- CoV-2 SP. HLA-A*74:01 allele is the best CTL epitope for SP. We identified seven B-cell epitopes specifically for SARS-CoV-2 SP. Conclusions: SARS-CoV-2 SP binding sites might be compatible with AMPN ligand binding sites. The limit score was detected for ligand binding sites of CAV1 and CAV2. Our findings might be critical for the further substantial study of vaccine production strategy.

scholarly journals Virtual Screening of Plant-Derived Compounds Against SARS-CoV-2 Viral Proteins Using Computational Tools

2020 ◽  
Author(s):  
Maria Antonela Zigolo ◽  
Matías Rivero Goytia ◽  
Hugo Ramiro Poma ◽  
Verónica Rajal ◽  
Veronica Patricia Irazusta
Keyword(s):  
Hydrophobic Interactions ◽  
Viral Proteins ◽  
Natural Compounds ◽  
Docking Studies ◽  
Binding Energies ◽  
Host Cells ◽  
Computational Tools ◽  
S Protein ◽  
Synthetic Drugs ◽  
Main Protease

<p>The new SARS-CoV-2, responsible for the COVID-19 pandemic, has been threatening public health worldwide for half a year. The aim of this work was to evaluate compounds of natural origin, mainly from medicinal plants, as potential SARS-CoV-2 inhibitors through docking studies. The viral spike (S) glycoprotein and the main protease M<sup>pro</sup>, involved in the recognition of virus by host cells and in viral replication, respectively, were the main molecular targets in this study. </p> <p>The best energy binding values for S protein were, in kcal/mol: -19.22 for glycyrrhizin, -17.84 for gitoxin, -12.05 for dicumarol, -10.75 for diosgenin, and -8.12 for delphinidin. For M<sup>pro</sup> were, in kcal/mol: -9.36 for spirostan, -8.75 for <i>N</i>-(3-acetylglycyrrhetinoyl)-2-amino-propanol, -8.41 for α-amyrin, -8.35 for oleanane, -8.11 for taraxasterol, and -8.03 for glycyrrhetinic acid. In addition, the synthetic drugs umifenovir, chloroquine, and hydroxychloroquine were used as controls for S protein, while atazanavir and nelfinavir were used for M<sup>pro</sup>. Key hydrogen bonds and hydrophobic interactions between natural compounds and the respective viral proteins were identified, allowing us to explain the great affinity obtained in those compounds with the lowest binding energies. These results suggest that these natural compounds could potentially be useful as drugs to be experimentally evaluated against COVID-19. </p>

scholarly journals The Omicron Variant Increases the Interactions of SARS-CoV-2 Spike Glycoprotein with ACE2

2021 ◽  
Author(s):  
Mert Golcuk ◽  
Ahmet Yildiz ◽  
Mert Gur
Keyword(s):  
Hydrophobic Interactions ◽  
Critical Role ◽  
Interaction Network ◽  
Binding Energies ◽  
Host Cells ◽  
Salt Bridges ◽  
Spike Glycoprotein ◽  
Angiotensin Converting Enzyme 2 ◽  
Poisson Boltzmann ◽  
Explicit Water

The Omicron variant (B.1.1.529) comprises 30 mutations on the spike glycoprotein (S), 15 of which are located on its receptor-binding domain (RBD_Omicron). RBD interacts with the peptidase domain (PD) of angiotensin-converting enzyme 2 (ACE2) receptors and plays a critical role in the host cell entry of the virus. We performed all-atom simulations of the RBD_Omicron-PD in the presence of explicit water and ions. Simulations showed a considerably more extensive interactions network between RBD_Omicron and PD compared to RBD_WT, comprising a 250%, 10% and -25% change in the total number of salt bridges, hydrophobic interactions, hydrogen bonds at the S-ACE2 interface, respectively. Using the conformations sampled in each our MD trajectories, binding energies of two sets of RBD_WT-PD and four sets of RBD_Omicron-PD simulations were calculated via the Molecular Mechanics Poisson-Boltzmann Surface Area (MMPBSA) method, estimating ~44% stronger binding energy for RBD_Omicron compared to RBD_WT. Our results suggest that an increase in the number of salt bridges in the S-ACE2 interface result in a higher binding strength of RBD to PD, which may result in a higher efficiency of the SARS-CoV-2 virus to infect host cells. Furthermore, RBD_Omicron exhibits a more dispersed interaction network on both sides of the RBD-PD interaction surface compared to WT.

scholarly journals Cryo-EM analysis of the HCoV-229E spike glycoprotein reveals dynamic prefusion conformational changes

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xiyong Song ◽  
Yuejun Shi ◽  
Wei Ding ◽  
Tongxin Niu ◽  
Limeng Sun ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Viral Entry ◽  
Therapeutic Antibody ◽  
Host Cells ◽  
Structural Comparison ◽  
Spike Glycoprotein ◽  
Closed Conformation ◽  
Open Conformation ◽  
Receptor Recognition ◽  
Antibody Design

AbstractCoronaviruses spike (S) glycoproteins mediate viral entry into host cells by binding to host receptors. However, how the S1 subunit undergoes conformational changes for receptor recognition has not been elucidated in Alphacoronavirus. Here, we report the cryo-EM structures of the HCoV-229E S trimer in prefusion state with two conformations. The activated conformation may pose the potential exposure of the S1-RBDs by decreasing of the interaction area between the S1-RBDs and the surrounding S1-NTDs and S1-RBDs compared to the closed conformation. Furthermore, structural comparison of our structures with the previously reported HCoV-229E S structure showed that the S trimers trended to open the S2 subunit from the closed conformation to open conformation, which could promote the transition from pre- to postfusion. Our results provide insights into the mechanisms involved in S glycoprotein-mediated Alphacoronavirus entry and have implications for vaccine and therapeutic antibody design.

scholarly journals Structural basis of SARS-CoV-2 spike protein induced by ACE2

2020 ◽  
Author(s):  
Tomer Meirson ◽  
David Bomze ◽  
Gal Markel
Keyword(s):  
Conformational Changes ◽  
Viral Entry ◽  
Structural Information ◽  
Active Form ◽  
Intramolecular Interactions ◽  
Host Cells ◽  
Structural Basis ◽  
S Protein ◽  
Binding Interface ◽  
Recent Emergence

AbstractMotivationThe recent emergence of the novel SARS-coronavirus 2 (SARS-CoV-2) and its international spread pose a global health emergency. The viral spike (S) glycoprotein binds the receptor (angiotensin-converting enzyme 2) ACE2 and promotes SARS-CoV-2 entry into host cells. The trimeric S protein binds the receptor using the distal receptor-binding domain (RBD) causing conformational changes in S protein that allow priming by host cell proteases. Unravelling the dynamic structural features used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal novel therapeutic targets. Using structures determined by X-ray crystallography and cryo-EM, we performed structural analysis and atomic comparisons of the different conformational states adopted by the SARS-CoV-2-RBD.ResultsHere, we determined the key structural components induced by the receptor and characterized their intramolecular interactions. We show that κ-helix (also known as polyproline II) is a predominant structure in the binding interface and in facilitating the conversion to the active form of the S protein. We demonstrate a series of conversions between switch-like κ-helix and β-strand, and conformational variations in a set of short α-helices which affect the proximal hinge region. This conformational changes lead to an alternating pattern in conserved disulfide bond configurations positioned at the hinge, indicating a possible disulfide exchange, an important allosteric switch implicated in viral entry of various viruses, including HIV and murine coronavirus. The structural information presented herein enables us to inspect and understand the important dynamic features of SARS-CoV-2-RBD and propose a novel potential therapeutic strategy to block viral entry. Overall, this study provides guidance for the design and optimization of structure-based intervention strategies that target SARS-CoV-2.

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