Submission EDJ-MED-d1555997

Topic automatically created for discussing the designs at:
https://covid.postera.ai/covid/submissions/EDJ-MED-d1555997

Hi @edgriffen (I’ll include @JSPEN who is thinking along similar lines with JOH-UNI-6e27fddc-1) I think that the 5-methyl will help push the isoquinoline out of coplanarity with the amide. However, interaction between the amide NH and 5-F will tend to bring isoquinoline and amide into coplanarity. The CSD structures: AFOZIG | AFOZOM | NAJNUJ | QIFGAP | AHEMEI may be of interest.

I’m aware of the challenge Pete - thanks for sharing the experimental structures AHEMEI at least suggests that they’re not absolutely flat. Andrew Leach (Manchester) also commented that there may be an H-bond from the isoquinoline 4-H to the carbonyl, we are currently making examples of both, so we can test the hypotheses.

Hi Ed,

While the CSD structures are helpful, my recommendation is to do torsional scans for the 5-substituted isoquinolinyl amides of interest. I would also recommend doing reference torsional scans for the pyridine, 4-methylpyridine, and unsubstituted isoquinoline equivalents (and making these visible to the Moonshot design community). The modern small-molecule force fields are typically derived from quantum mechanical calculations and I would recommend running the torsional scans using the theoretical model used to derive the force field. This means that you don’t have to worry about how well the force field parameterization captures the QM calculation. Andrew should easily be able to do the calculations if he has the time and I’ll also mention @JohnChodera given his expertise in the force field area. In general, I would be wary of force field parameters for fluorine.