A large collaborative initiative including research groups from the CMD Oxford, Diamond Light Source, the Weizmann Institute in Israel, Sloan Kettering Centre for Cancer Research and PostEra have contributed to the global anti- COVID-19 effort. Based on fragment screening hits they aim to develop novel small molecule inhibitors targeting SARS-CoV-2 3CL main protease.
Members from Frank von Delft’s SGC-based Protein Crystallography and Diamond Light Source-based XChem groups joined forces with other research groups at Diamond Light Source to contribute to the global anti- COVID-19 effort. Since mid March, (including a phenomenal 72 hours going from crystallisation to testing 600 compounds by XChem) members from Frank von Delft’s SGC-based Protein Crystallography and Diamond Light Source-based XChem groups has been working on the SARS-CoV-2 main protease (Mpro), succeeding in obtaining a high-resolution structure (PDB ID: 6YB7) and performing fragment screening identifying 66 fragments that bind to the active site. All currently available structures have been deposited in the Protein Data Bank, and can also be accessed and analysed through the Fragalysis cloud computing platform.
This data has been used by the COVID Moonshot collaboration, which combines international efforts across academia and industry to follow up on the identified hits and ultimately develop effective and easily synthesized anti-COVID drugs. The first round of compounds have now been synthesised and showed antiviral activity in cellular assays. The BRC translational team is supporting further early translational development of novel antiviral compounds.
Guo J, Douangamath A, Song W, Coker A, Chan AWE, Wood SP, Cooper JB, Resnick E, London N, von Delft F In crystallo-screening for discovery of human norovirus 3C-like protease inhibitors. J Struct Biol X. 2020 Jul 16;4:100031.doi: 10.1016/j.yjsbx.2020.100031. eCollection 2020.
Chodera J, Lee AA, London N, von Delft F. Crowdsourcing drug discovery for pandemics. Nat Chem. 2020 Jul;12(7):581. doi: 10.1038/s41557-020-0496-2.
Douangamath A, Fearon D, Gehrtz P, Krojer T, Lukacik P, Owen CD, Resnick E, Strain-Damerell C, Aimon A, Ábrányi-Balogh P, Brandaõ-Neto J, Carbery A, Davison G, Dias A, Downes TD, Dunnett L, Fairhead M, Firth JD, Jones SD, Keely A, Keserü GM, Klein HF, Martin MP, Noble MEM, O’Brien P, Powell A, Reddi R, Skyner R, Snee M, Waring MJ, Wild C, London N, von Delft F, Walsh MA. Crystallographic and electrophilic fragment screening of the SARS-CoV-2 main protease. bioRxiv 2020.05.27.118117; doi: https://doi.org/10.1101/2020.05.27.118117.