Exploring the Fatty Acid Binding Pocket in the SARS-CoV-2 Spike Protein – Confirmed and Potential Ligands

Queirós-Reis, Luís; Mesquita, João R.; Brancale, Andrea; Bassetto, Marcella

doi:10.1021/acs.jcim.3c00803

Cited by 2 publications

(2 citation statements)

References 59 publications

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“…Given a significant number of cryptic binding pockets on the S surface, it is important to identify and validate targeted allosteric pockets which can facilitate understanding of the inhibitory mechanisms. In this context, the experimental validation of the LA allosteric pocket as a primary target for many active compounds binding to this site with high affinity and stabilizing the inactive conformation of the S protein exemplifies targeted allosteric intervention [64]. Our study indicated that allosteric molecules may target the conserved inter-protomer allosteric pocket (site A) and RBD-RBD pocket (site B) that includes residues from the LA binding site.…”

Section: Ensemble Docking and Mm-gbsa Binding Free Energy Calculation...mentioning

confidence: 74%

“…There are several experimentally validated allosteric inhibitors that bind to the LA binding pocket and exert a biological activity by allosterically inhibiting the S-ACE2 interaction, as was determined by SPR and cryo-EM analyses [36.37]. Several studies described other potential allosteric ligands with a confirmed binding in vitro assays showing a good occupation of the LA pocket, indicating that compounds binding to this allosteric site with high affinity have the potential to stabilize the inactive conformation of the S protein [64].…”

Section: Resultsmentioning

confidence: 99%

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Exploring Binding Pockets in the Conformational States of the SARS-CoV-2 Spike Trimers for the Screening of Allosteric Inhibitors Using Molecular Simulations and Ensemble-Based Ligand Docking

Gupta,

Verkhivker

2024

IJMS

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Understanding mechanisms of allosteric regulation remains elusive for the SARS-CoV-2 spike protein, despite the increasing interest and effort in discovering allosteric inhibitors of the viral activity and interactions with the host receptor ACE2. The challenges of discovering allosteric modulators of the SARS-CoV-2 spike proteins are associated with the diversity of cryptic allosteric sites and complex molecular mechanisms that can be employed by allosteric ligands, including the alteration of the conformational equilibrium of spike protein and preferential stabilization of specific functional states. In the current study, we combine conformational dynamics analysis of distinct forms of the full-length spike protein trimers and machine-learning-based binding pocket detection with the ensemble-based ligand docking and binding free energy analysis to characterize the potential allosteric binding sites and determine structural and energetic determinants of allosteric inhibition for a series of experimentally validated allosteric molecules. The results demonstrate a good agreement between computational and experimental binding affinities, providing support to the predicted binding modes and suggesting key interactions formed by the allosteric ligands to elicit the experimentally observed inhibition. We establish structural and energetic determinants of allosteric binding for the experimentally known allosteric molecules, indicating a potential mechanism of allosteric modulation by targeting the hinges of the inter-protomer movements and blocking conformational changes between the closed and open spike trimer forms. The results of this study demonstrate that combining ensemble-based ligand docking with conformational states of spike protein and rigorous binding energy analysis enables robust characterization of the ligand binding modes, the identification of allosteric binding hotspots, and the prediction of binding affinities for validated allosteric modulators, which is consistent with the experimental data. This study suggested that the conformational adaptability of the protein allosteric sites and the diversity of ligand bound conformations are both in play to enable efficient targeting of allosteric binding sites and interfere with the conformational changes.

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Section: Ensemble Docking and Mm-gbsa Binding Free Energy Calculation...mentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Exploring Binding Pockets in the Conformational States of the SARS-CoV-2 Spike Trimers for the Screening of Allosteric Inhibitors Using Molecular Simulations and Ensemble-Based Ligand Docking

Gupta,

Verkhivker

2024

IJMS

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Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination

Voss,

Mallory,

Byrne

et al. 2024

Cell Reports Medicine

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Exploring the Fatty Acid Binding Pocket in the SARS-CoV-2 Spike Protein – Confirmed and Potential Ligands

Cited by 2 publications

References 59 publications

Exploring Binding Pockets in the Conformational States of the SARS-CoV-2 Spike Trimers for the Screening of Allosteric Inhibitors Using Molecular Simulations and Ensemble-Based Ligand Docking

Exploring Binding Pockets in the Conformational States of the SARS-CoV-2 Spike Trimers for the Screening of Allosteric Inhibitors Using Molecular Simulations and Ensemble-Based Ligand Docking

Hybrid immunity to SARS-CoV-2 arises from serological recall of IgG antibodies distinctly imprinted by infection or vaccination

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