tetano
Editor, Senior Moderator
J Med Chem
. 2025 Oct 12.
doi: 10.1021/acs.jmedchem.5c01199. Online ahead of print. Discovery of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 Main Protease through Computer-Aided Drug Design
Atsutoshi Okabe[SUP] 1 [/SUP], Daniel W Carney[SUP] 2 [/SUP], Michiko Tawada[SUP] 1 [/SUP], Thamina Akther[SUP] 1 [/SUP], Jumpei Aida[SUP] 1 [/SUP], Terufumi Takagi[SUP] 1 [/SUP], Douglas R Dougan[SUP] 2 [/SUP], Abba E Leffler[SUP] 3 [/SUP], Jeffrey A Bell[SUP] 3 [/SUP], Leah Frye[SUP] 4 [/SUP], Eugene R Hickey[SUP] 3 [/SUP], Mallareddy Komandla[SUP] 2 [/SUP], Will Tao[SUP] 2 [/SUP], Jangir Selimkhanov[SUP] 2 [/SUP], Kazuko Yonemori[SUP] 1 [/SUP], Edcon Chang[SUP] 2 [/SUP], Kumar Saikatendu[SUP] 2 [/SUP], Atsuko Ochida[SUP] 1 [/SUP]
Affiliations
The COVID-19 pandemic has highlighted a clear need to ensure rapid and equitable global access to health interventions in preparation for future coronavirus-driven pandemics. Here, we report the discovery of highly potent noncovalent inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) with pan-coronavirus (pan-CoV) Mpro inhibition through computer-aided drug design. Virtual screening led to the identification of a noncovalent hit compound with a piperazine core. Structure-guided scaffold morphing provided a novel trisubstituted piperidine core. Free energy perturbation (FEP)-guided designs, with induced-fit of Met49/Met165 and Gln189, resulted in the identification of highly potent compound 30, which exhibits pan-CoV Mpro inhibition and cellular antiviral efficacy against the SARS-CoV-2 omicron variant. The optimized lead compound 30 was characterized by in vitro ADME/Tox assays and in vivo mouse pharmacokinetics. These findings suggest that compound 30 could be an addition to the repertoire of tools used to support future pandemic preparedness.
. 2025 Oct 12.
doi: 10.1021/acs.jmedchem.5c01199. Online ahead of print. Discovery of Highly Potent Noncovalent Inhibitors of SARS-CoV-2 Main Protease through Computer-Aided Drug Design
Atsutoshi Okabe[SUP] 1 [/SUP], Daniel W Carney[SUP] 2 [/SUP], Michiko Tawada[SUP] 1 [/SUP], Thamina Akther[SUP] 1 [/SUP], Jumpei Aida[SUP] 1 [/SUP], Terufumi Takagi[SUP] 1 [/SUP], Douglas R Dougan[SUP] 2 [/SUP], Abba E Leffler[SUP] 3 [/SUP], Jeffrey A Bell[SUP] 3 [/SUP], Leah Frye[SUP] 4 [/SUP], Eugene R Hickey[SUP] 3 [/SUP], Mallareddy Komandla[SUP] 2 [/SUP], Will Tao[SUP] 2 [/SUP], Jangir Selimkhanov[SUP] 2 [/SUP], Kazuko Yonemori[SUP] 1 [/SUP], Edcon Chang[SUP] 2 [/SUP], Kumar Saikatendu[SUP] 2 [/SUP], Atsuko Ochida[SUP] 1 [/SUP]
Affiliations
- PMID: 41076627
- DOI: 10.1021/acs.jmedchem.5c01199
The COVID-19 pandemic has highlighted a clear need to ensure rapid and equitable global access to health interventions in preparation for future coronavirus-driven pandemics. Here, we report the discovery of highly potent noncovalent inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) with pan-coronavirus (pan-CoV) Mpro inhibition through computer-aided drug design. Virtual screening led to the identification of a noncovalent hit compound with a piperazine core. Structure-guided scaffold morphing provided a novel trisubstituted piperidine core. Free energy perturbation (FEP)-guided designs, with induced-fit of Met49/Met165 and Gln189, resulted in the identification of highly potent compound 30, which exhibits pan-CoV Mpro inhibition and cellular antiviral efficacy against the SARS-CoV-2 omicron variant. The optimized lead compound 30 was characterized by in vitro ADME/Tox assays and in vivo mouse pharmacokinetics. These findings suggest that compound 30 could be an addition to the repertoire of tools used to support future pandemic preparedness.