Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/MIC-UNK-5d22d78d
Hi @miko_a I certainly agree that the S1’ subsite can accommodate much larger substituents than those in the PET-UNK-824b5c6a and that is actually a big part of the challenge to exploiting this region of the protein molecular surface. The other difficulty is that the ‘floor’ S1’ is flat and relatively non-polar and my view is that the S4 subsite would be much more promising. One of the weaknesses in the chromane scaffold (and other series such as tetrahydroisoquinolines in which the parent phenylacetamide structure is annulated with a link between the benzylic carbon and the P2 benzene ring) is that access to the S4 subsite appears to be restricted.
What I have been attempting to do in the S1’ subsite is to engineer non-polar contact with the floor of the S1’ subsite while presenting polar functionality to either solvent or the oxyanion hole region. This is the best approach that I can think of and there may well be better options.
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