6533b830fe1ef96bd1297136
RESEARCH PRODUCT
Computational simulations on the binding and reactivity of a nitrile inhibitor of the SARS-CoV-2 main protease.
J. Javier Ruiz-perníaCarlos A. Ramos-guzmánIñaki Tuñónsubject
Reaction mechanismNitrileLactamsProlineStereochemistrymedicine.medical_treatmentMolecular Dynamics SimulationCatalysischemistry.chemical_compoundMolecular dynamicsLeucineCatalytic DomainNitrilesMaterials ChemistrymedicineMoleculeHumansReactivity (chemistry)Protease InhibitorsBinding siteCoronavirus 3C ProteasesProteaseBinding SitesSARS-CoV-2Metals and AlloysCOVID-19General ChemistrySurfaces Coatings and FilmsElectronic Optical and Magnetic MaterialschemistryCovalent bondCeramics and CompositesQuantum TheoryThermodynamicsdescription
We present a detailed computational analysis of the binding mode and reactivity of the novel oral inhibitor PF-07321332 developed against the SARS-CoV-2 3CL protease. Alchemical free energy calculations suggest that positions P3 and P4 could be susceptible to improvement in order to get a larger binding strength. QM/MM simulations unveil the reaction mechanism for covalent inhibition, showing that the nitrile warhead facilitates the recruitment of a water molecule for the proton transfer step.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-09-09 | Chemical communications (Cambridge, England) |