Valproate-coenzyme A conjugate blocks opening of receptor binding domains in the spike trimer of SARS-CoV-2 through an allosteric mechanism

A computationally designed ACE2 decoy has broad efficacy against SARS-CoV-2 omicron variants and related viruses in vitro and in vivo

“…In conclusion, we used an orthogonal approach comprised of computational protein design, MD simulations, and free energy calculations to design an ACE2 mutant, FLIF , that exhibited tight binding to SARS-CoV-2 delta and omicron variants, displayed robust therapeutic utility against a broad range of SARS-CoV-2 variants and sarbecoviruses, and neutralized the dominant circulating variant worldwide, omicron BA.5, in vitro and in vivo. Orthogonal approaches combining computational and experimental methods remain promising for discovering small molecule and protein inhibitors of SARS-CoV-2 87 , 88 . Recently, Maschietto et al 87 used a computational approach to discover a valproate-coenzyme A conjugate that works allosterically to stabilize the RBDs in the trimeric “down” configuration to prevent binding to ACE2.…”

“…Orthogonal approaches combining computational and experimental methods remain promising for discovering small molecule and protein inhibitors of SARS-CoV-2 87 , 88 . Recently, Maschietto et al 87 used a computational approach to discover a valproate-coenzyme A conjugate that works allosterically to stabilize the RBDs in the trimeric “down” configuration to prevent binding to ACE2. The approach described herein emphasizes how computational methods have become sufficiently accurate for the design of therapeutics against viral protein targets and further shows the utility of engineered ACE2 decoys to remain effective against future SARS-CoV-2 variants.…”

Inhibition of Human Coronaviruses by Combinations of Host-Targeted and Direct-Acting Antivirals

“…Nevertheless, a direct interaction of these compounds with viral components cannot be excluded. Indeed, is has been recently reported that a lead compound (3-oxo-valproatecoenzyme A conjugate) can stabilize the SARS-CoV-2 spike trimer with RBDs in the down conformation, likely impairing binding to the ACE2 receptor of the host cell ( 55 ).…”

Occupancy Analysis of Water Molecules inside Channels within 25 Å Radius of the Oxygen-Evolving Center of Photosystem II in Molecular Dynamics Simulations

“…The occupancy of individual water positions was determined from the analysis of the final 50 ns of the S 1 - and S 2 -state full PSII monomer simulations. A total of 12,500 snapshots were combined into a single structure, which was then used to simulate a PDF using a unit scattering factor (such as a neutron scattering factor) using the SFALL program − within the CCP4 software package, as described elsewhere. − A sample CCP4 code is given in the Supporting Information . All hydrogens were renamed as deuterons for enabling the use of the neutron scattering library without a change in their positions (one could modify the neutron scattering factor in the library to make H atoms have a unit scattering value).…”