Early SARS-CoV-2 drug discovery
What is it about?
Fragment screening is used to find small molecules that bind to drug targets. We have used it on a form of the main protease target of SARS-CoV-2 with a binding pocket that is "locked" in a more open conformation. Our fragment screen identified new small molecules binding to the protease, but also showed that the same small molecule can bind in different ways depending on the conformation of the target that is used for screening.
Why is it important?
Our newly identified fragments and their crystal structures bound to their target add to the understanding of the key binding interactions available for guiding the design of SARS-CoV-2 protease inhibitors. The comparison of reference inhibitors binding to different conformations of the target binding site confirms the importance of considering protein dynamics in structure guided drug discovery.