Deciphering the Impact of Mutations on the Binding Efficacy of SARS-CoV-2 Omicron and Delta Variants With Human ACE2 Receptor

Khan, Alamgir; Khan, Salman Ali; Zia, Komal; Altowyan, Mezna Saleh; Barakat, Assem; Ul-Haq, Zaheer

doi:10.3389/fchem.2022.892093

Cited by 14 publications

(20 citation statements)

References 41 publications

(45 reference statements)

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“…The higher binding affinity of the omicron variant to the ACE2 compared to the original strain as found in our study is consistent with the results of the MD and docking based computational studies existing in the literature. [ 60 , 61 , 62 , 63 , 64 ] On the other hand, experimental studies report differing results. The surface plasmon resonance (SPR) based experimental studies also support our findings that the binding affinity of the omicron variant to the ACE2 is higher than that of the original strain [ 65 , 66 ] , while a noncompetitive enzyme‐linked immunosorbent assay (ELISA) based experimental study reported a comparable binding affinity for the omicron variant and the original strain.…”

Section: Resultsmentioning

confidence: 99%

Computation of the Binding Energies between Human ACE2 and Spike RBDs of the Original Strain, Delta and Omicron Variants of the SARS‐CoV‐2: A DFT Simulation Approach

Yamaçli

Avcı

2022

Advcd Theory and Sims

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The receptor binding domain (RBD) of SARS‐CoV‐2 binds to human ACE2 leading to infection. In this study, the complexes that are formed by the attachment of the SARS‐CoV‐2 spike RBDs of the original strain, delta and omicron variants to the human ACE2 are investigated via density functional theory (DFT) simulations to obtain binding energies. The DFT computations are performed without fragmenting the interfaces to involve longer‐range interactions for improved accuracy, which is one of the primary features of the approach used in this study. Basis set superposition error corrections and van der Waals dispersions are also included in the DFT simulations. The binding energies of the SARS‐CoV‐2 spike RBDs of the original strain, delta and omicron variants to the human ACE2 are computed as −4.76, −6.68, and −11.77 eV, respectively. These binding energy values indicate that the binding of the omicron variant to the ACE2 is much more favorable than the binding of the original strain and the delta variant, which constitute a molecular reason for the takeover of the omicron variant. The binding energies and the decomposition of these energies found in this study are expected to aid in the development of neutralizing agents.

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Section: Resultsmentioning

confidence: 99%

Computation of the Binding Energies between Human ACE2 and Spike RBDs of the Original Strain, Delta and Omicron Variants of the SARS‐CoV‐2: A DFT Simulation Approach

Yamaçli

Avcı

2022

Advcd Theory and Sims

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“…However, there were some discrepancies among these studies on the binding efficiencies of these variants. The most of computational studies predicted that RBD of Omicron showed stronger binding to hACE2 receptor compared to RBD of wild and Delta respectively [9][10][11][12][13][14][15]. Leyun Wu et al, reported that RBD of Omicron had a weak affinity to hACE2 receptor compared to RBD of Delta, but similar to RBD of wild affinity by molecular dynamics (MD) simulations analysis [16].…”

Section: Introductionmentioning

confidence: 99%

Correlating the differences in the receptor binding domain of SARS-CoV-2 spike variants on their interactions with human ACE2 receptor

Mahalingam¹,

Arjunan²,

Periasami³

et al. 2022

Preprint

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Spike protein of SARS-CoV-2 variants play critical role in the infection and transmission through its interaction with hACE2 receptor. Prior findings using molecular docking and biomolecular studies reported varied findings on the difference in the interactions among the spike variants with hACE2 receptor. Hence, it is a prerequisite to understand these interactions in a more precise manner. To this end, firstly, we performed ELISA with trimeric spike proteins of Wild (Wuhan Hu-1), Delta, C.1.2 and Omicron variants. Further, to study the interactions in a more specific manner by mimicking the natural infection, we developed hACE2 receptor expressing HEK-293T cell line and evaluated binding efficiencies of the variants and competitive binding of spike variants with D614G spike pseudotyped virus. In lines with the existing findings, we observed that Omicron had higher binding efficiency compared to Delta in both ELISA and Cellular models. Intriguingly, we found that cellular models could differentiate the subtle differences between the closely related C.1.2 and Delta in their binding to hACE2. From the analysis in receptor binding domain (RBD) revealed that a single common modification, N501Y, present in both Omicron and C.1.2 is driving the enhanced spike binding to the receptor and showed two-fold superior competitive binding than Delta. Our study using cellular model provides a precise method to evaluate the binding interactions between spike sub-lineages to hACE2 receptors and signifies the role of single common modification N501Y in RBD towards imparting superior binding efficiencies. Our approach would be instrumental in understanding the disease progression and developing therapeutics.

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“…Similarly, Tyr41 also mediates π-π stacking interaction with Tyr501 of RBD. Phe486 from RBD mediates hydrophobic interactions with a small hydrophobic pocket in the interface formed by Phe28, Leu79, Met82, and Tyr83 of hACE2 [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

Cheminformatics-Based Discovery of Potential Chemical Probe Inhibitors of Omicron Spike Protein

Khan

Zia

et al. 2022

IJMS

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During the past two decades, the world has witnessed the emergence of various SARS-CoV-2 variants with distinct mutational profiles influencing the global health, economy, and clinical aspects of the COVID-19 pandemic. These variants or mutants have raised major concerns regarding the protection provided by neutralizing monoclonal antibodies and vaccination, rates of virus transmission, and/or the risk of reinfection. The newly emerged Omicron, a genetically distinct lineage of SARS-CoV-2, continues its spread in the face of rising vaccine-induced immunity while maintaining its replication fitness. Efforts have been made to improve the therapeutic interventions and the FDA has issued Emergency Use Authorization for a few monoclonal antibodies and drug treatments for COVID-19. However, the current situation of rapidly spreading Omicron and its lineages demands the need for effective therapeutic interventions to reduce the COVID-19 pandemic. Several experimental studies have indicated that the FDA-approved monoclonal antibodies are less effective than antiviral drugs against the Omicron variant. Thus, in this study, we aim to identify antiviral compounds against the Spike protein of Omicron, which binds to the human angiotensin-converting enzyme 2 (ACE2) receptor and facilitates virus invasion. Initially, docking-based virtual screening of the in-house database was performed to extract the potential hit compounds against the Spike protein. The obtained hits were optimized by DFT calculations to determine the electronic properties and molecular reactivity of the compounds. Further, MD simulation studies were carried out to evaluate the dynamics of protein–ligand interactions at an atomistic level in a time-dependent manner. Collectively, five compounds (AKS-01, AKS-02, AKS-03, AKS-04, and AKS-05) with diverse scaffolds were identified as potential hits against the Spike protein of Omicron. Our study paves the way for further in vitro and in vivo studies.

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Deciphering the Impact of Mutations on the Binding Efficacy of SARS-CoV-2 Omicron and Delta Variants With Human ACE2 Receptor

Cited by 14 publications

References 41 publications

Computation of the Binding Energies between Human ACE2 and Spike RBDs of the Original Strain, Delta and Omicron Variants of the SARS‐CoV‐2: A DFT Simulation Approach

Computation of the Binding Energies between Human ACE2 and Spike RBDs of the Original Strain, Delta and Omicron Variants of the SARS‐CoV‐2: A DFT Simulation Approach

Correlating the differences in the receptor binding domain of SARS-CoV-2 spike variants on their interactions with human ACE2 receptor

Cheminformatics-Based Discovery of Potential Chemical Probe Inhibitors of Omicron Spike Protein

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