Is the Stalk of the SARS-CoV-2 Spike Protein Druggable?

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    Abstract

    The spike protein is key to SARS-CoV-2 high infectivity because it facilitates the receptor binding domain (RBD) encounter with ACE2. As targeting subunit S1 has not yet delivered an ACE2-binding inhibitor, we have assessed the druggability of the conserved segment of the spike protein stalk within subunit S2 by means of an integrated computational approach that combines the molecular docking of an optimized library of fragments with high-throughput molecular dynamics simulations. The high propensity of the spike protein to mutate in key regions that are responsible for the recognition of the human angiotensin-converting enzyme 2 (hACE2) or for the recognition of antibodies, has made subunit S1 of the spike protein difficult to target. Despite the inherent flexibility of the stalk region, our results suggest two hidden interhelical binding sites, whose accessibility is only partially hampered by glycan residues.
    Original languageEnglish
    Article number2789
    Number of pages12
    JournalViruses
    Volume14
    Issue number12
    DOIs
    Publication statusPublished - 14 Dec 2022

    Bibliographical note

    This article is an open access article distributed under the terms and
    conditions of the Creative Commons Attribution (CC BY) license (https://
    creativecommons.org/licenses/by/4.0/).

    Keywords

    • SARS-CoV-2
    • fragment-based drug discovery
    • molecular dynamics
    • spike protein

    ASJC Scopus subject areas

    • Infectious Diseases
    • Virology

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