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Would It Be Possible to Stabilize Prefusion SARS-COV-2 Spikes with Ligands?
preprintsubmitted on 20.12.2020, 10:18 and posted on 22.12.2020, 06:41 by Julio Coll
The infection by Severe Acute Respiratory Syndrome coronavirus (SARS)-CoV2 could be inhibited in vitro by mutations stabilizing their spike (S) native conformation in prefusion states, as reported by several authors. However, the possible S stabilization by binding-ligands, rather than by mutations, have not been computationally explored, nor it is known if that will be possible. Therefore, to first explore these possibilities, a binding target for predictive programs was focused to where the inhibiting mutations were described in the S coronavirus protein, in particular to the “spring-loaded switch-folding” (SLSF) segment of the S2 subunit, whose prefusion unfolding/refolding is required for viral/host membrane fusion. Similar SLSF prefusion mechanisms have been described in many other enveloped viruses. Results of a double computational screening of hundred of thousands of natural compounds for binding to wild-type SLSF conformer, predicted more leads in the low nM range for trimers than for monomers. Further ranked by the number of bound SLSF-conformers, some of the derived top-leads were predicted that may deserve experimental validation. Additionally, thousands of drugs were also included into the screening, resulting in a few top-lead drugs predicted to bind SLSF targets in the low nM range. All these potentially interacting S-ligands, similar structures and/or chemically improved designs, could be used to experimentally find out whether it will be possible to use them for inhibiting fusion and infection, offer new tools to investigate prefusion mechanism(s) and may contribute to therapeutic purposes.