Abstract
Starting from our previous finding of 14 known drugs as inhibitors of the main protease (Mpro) of SARS-CoV-2, the virus responsible for COVID-19, we have redesigned the weak hit perampanel to yield multiple noncovalent, nonpeptidic inhibitors with ca. 20 nM IC50 values in a kinetic assay. Free-energy perturbation (FEP) calculations for Mpro-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered the potent analogues. The design efforts were confirmed and augmented by determination of high-resolution X-ray crystal structures for five analogues bound to Mpro. Results of cell-based antiviral assays further demonstrated the potential of the compounds for treatment of COVID-19. In addition to the possible therapeutic significance, the work clearly demonstrates the power of computational chemistry for drug discovery, especially FEP-guided lead optimization.
Highlights
The coronavirus SARS-CoV-2, the cause of the COVID-19 pandemic,[1] encodes several enzymes that are essential to its ability to replicate.[2,3] After cell entry, viral RNA is translated by host ribosomes into two polyproteins that are cleaved to produce the viral proteins that are needed for assembling new virions
Crystal structures of main protease (Mpro) from SARS-CoV-2 have quickly emerged along with initial reports of inhibitors.[6−11] As for the earlier virus, the designed inhibitors have largely been peptide-like with incorporation of a reactive warhead that covalently binds to the catalytic cysteine, Cys[145]
We report successful execution of the latter strategy starting from a weak hit, the anti-epileptic drug perampanel, in the kinetic assay
Summary
The coronavirus SARS-CoV-2, the cause of the COVID-19 pandemic,[1] encodes several enzymes that are essential to its ability to replicate.[2,3] After cell entry, viral RNA is translated by host ribosomes into two polyproteins that are cleaved to produce the viral proteins that are needed for assembling new virions. Crystal structures of Mpro from SARS-CoV-2 have quickly emerged along with initial reports of inhibitors.[6−11] As for the earlier virus, the designed inhibitors have largely been peptide-like with incorporation of a reactive warhead that covalently binds to the catalytic cysteine, Cys[145]. These features are generally not optimal for drug development owing to potential proteolytic degradation, limited antiviral activity, and toxicities from off-target covalent modification of other biomolecules.[5]. The optimization proceeded extraordinarily rapidly owing to the use of free-energy perturbation (FEP) calculations to guide the choices of structural modifications.[13−17]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
