In addition to the well-established GPCR and protease targets, the SpotXplorer0 pilot library was screened against more challenging current targets, including the histone methyltransferase SETD2, as well as the main protease 3CLPro and the macrodomain NSP3 of the SARS-CoV-2 virus, which is responsible for the ongoing COVID-19 pandemic. Here, SETD2 is linked to COVID-19.