biostudies-literatureSchuller MOxford University Challenge Seed FundAlzheimer’s Research UKWellcome TrustBiotechnology and Biological Sciences Research CouncilOvarian Cancer Research Alliance324https://www.ebi.ac.uk/biostudies/studies/S-EPMC9965906biostudies-literatureUnknown12(2)The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibioPathogens (Basel, Switzerland)Discovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors.PMC9965906USCF 456BB/W016613/1ARUK-2021DDI-OX813369210634/Z/18/Z210634BB/R007195/1223107Schuller MAhel IDe Cesco Svon Delft FBrennan PEZarganes-Tzitzikas TFearon DFedorov OBennett JfalseDiscovery and Development Strategies for SARS-CoV-2 NSP3 Macrodomain Inhibitors.The worldwide public health and socioeconomic consequences caused by the COVID-19 pandemic highlight the importance of increasing preparedness for viral disease outbreaks by providing rapid disease prevention and treatment strategies. The NSP3 macrodomain of coronaviruses including SARS-CoV-2 is among the viral protein repertoire that was identified as a potential target for the development of antiviral agents, due to its critical role in viral replication and consequent pathogenicity in the host. By combining virtual and biophysical screening efforts, we discovered several experimental small molecules and FDA-approved drugs as inhibitors of the NSP3 macrodomain. Analogue characterisation of the hit matter and crystallographic studies confirming binding modes, including that of the antibio2023-01-01T00:00:00Z2023 Feb2026-05-16T03:12:37.478Z2025-02-18T23:44:23.044ZS-EPMC99659063683959510.3390/pathogens12020324