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bioRxiv · 10.1101/2022.10.06.511069

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

Pipito, L.·Reynolds, C. A.·Deganutti, G.
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Abstract

The SARS-CoV-2 virus spike protein (SP) is the vector of the virus infectivity. The high propensity to mutate in key regions responsible for the recognition of the human angiotensinconverting enzyme 2 (hACE2) or the antibodies produced by the immune system following infection or vaccination makes subunit 1 of the SP a difficult to target and, to date, efforts have not delivered any ACE2 binding inhibitor yet. The inherent flexibility of the stalk region, within subunit S2, is key to SARS-CoV-2 high infectivity because it facilitates the receptor binding domain encounter with ACE2. Thus, it could be a valuable therapeutic target. By employing a fragment-based strategy, we computationally studied the druggability of the conserved part of the SP stalk by means of an integrated approach that combines molecular docking with high-throughput molecular dynamics simulations. Our results suggest that the druggability of the stalk is challenging and provide the structural basis for such difficulty.

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Pipito, L., Reynolds, C. A., Deganutti, G.. 2022-10-06. Is The Stalk of the SARS-CoV-2 Spike Protein Druggable?. https://doi.org/10.1101/2022.10.06.511069

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