tetano
Editor, Senior Moderator
RSC Med Chem
. 2024 Apr 29;15(6):2146-2159.
doi: 10.1039/d4md00106k. eCollection 2024 Jun 19. Identification of SARS-CoV-2 Mpro inhibitors through deep reinforcement learning for de novo drug design and computational chemistry approaches
Julien Hazemann[SUP] 1 2 [/SUP], Thierry Kimmerlin[SUP] 2 [/SUP], Roland Lange[SUP] 2 [/SUP], Aengus Mac Sweeney[SUP] 2 [/SUP], Geoffroy Bourquin[SUP] 2 [/SUP], Daniel Ritz[SUP] 2 [/SUP], Paul Czodrowski[SUP] 1 [/SUP]
Affiliations
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease (COVID-19) since its emergence in December 2019. As of January 2024, there has been over 774 million reported cases and 7 million deaths worldwide. While vaccination efforts have been successful in reducing the severity of the disease and decreasing the transmission rate, the development of effective therapeutics against SARS-CoV-2 remains a critical need. The main protease (Mpro) of SARS-CoV-2 is an essential enzyme required for viral replication and has been identified as a promising target for drug development. In this study, we report the identification of novel Mpro inhibitors, using a combination of deep reinforcement learning for de novo drug design with 3D pharmacophore/shape-based alignment and privileged fragment match count scoring components followed by hit expansions and molecular docking approaches. Our experimentally validated results show that 3 novel series exhibit potent inhibitory activity against SARS-CoV-2 Mpro, with IC[SUB]50[/SUB] values ranging from 1.3 μM to 2.3 μM and a high degree of selectivity. These findings represent promising starting points for the development of new antiviral therapies against COVID-19.
. 2024 Apr 29;15(6):2146-2159.
doi: 10.1039/d4md00106k. eCollection 2024 Jun 19. Identification of SARS-CoV-2 Mpro inhibitors through deep reinforcement learning for de novo drug design and computational chemistry approaches
Julien Hazemann[SUP] 1 2 [/SUP], Thierry Kimmerlin[SUP] 2 [/SUP], Roland Lange[SUP] 2 [/SUP], Aengus Mac Sweeney[SUP] 2 [/SUP], Geoffroy Bourquin[SUP] 2 [/SUP], Daniel Ritz[SUP] 2 [/SUP], Paul Czodrowski[SUP] 1 [/SUP]
Affiliations
- PMID: 38911172
- PMCID: PMC11187573
- DOI: 10.1039/d4md00106k
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a global pandemic of coronavirus disease (COVID-19) since its emergence in December 2019. As of January 2024, there has been over 774 million reported cases and 7 million deaths worldwide. While vaccination efforts have been successful in reducing the severity of the disease and decreasing the transmission rate, the development of effective therapeutics against SARS-CoV-2 remains a critical need. The main protease (Mpro) of SARS-CoV-2 is an essential enzyme required for viral replication and has been identified as a promising target for drug development. In this study, we report the identification of novel Mpro inhibitors, using a combination of deep reinforcement learning for de novo drug design with 3D pharmacophore/shape-based alignment and privileged fragment match count scoring components followed by hit expansions and molecular docking approaches. Our experimentally validated results show that 3 novel series exhibit potent inhibitory activity against SARS-CoV-2 Mpro, with IC[SUB]50[/SUB] values ranging from 1.3 μM to 2.3 μM and a high degree of selectivity. These findings represent promising starting points for the development of new antiviral therapies against COVID-19.