Conformational preferences of methoxy in 4- methoxychromane

I’ll mention @alphalee @frankvondelft @JohnChodera @londonir @mc-robinson @edgriffen @RGlen in case this material is of interest.

I’ve run a couple of CSD searches in order to better understand the conformational preferences of the methoxy substituent of PET-UNK-29afea89-2. The dihedral angle profiles shown in the graphic below indicate that the oxygen of the methoxy group tends to eclipse the amide NH. Although I would not regard interaction between methoxy oxygen and NH as a proper hydrogen bond, the interaction has the potential to prevent the amide NH as a hydrogen bond donor (one can think in terms of a secondary electrostatic interaction between the methoxy oxygen and any hydrogen bond acceptor that the amide NH happens to interact with). I speculate that this may be the basis for any benefits of the methoxy with respect to translation of enzyme inhibition to activity in cell-based assays (maybe the amide NH is recognized by a transporter?).

Here are the dihedral angle distributions (the bonds that define each dihedral are constrained to be acyclic)

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There are numerous examples over the last 40 years where the conformers of drug-like molecules in small molecule crystal structures are not relevant because the crystal packing energetics takes priority over any conformational energy preferences when these are small. The early rebuttals focused on NMR data rather than calculations.

The more I think about this problem the more crucial I believe it is to move away the idea that the ideal geometry for the best energetics for binding is important. We should be looking at free energies - and of course changes in free energies from solution etc. That information isnt available in small molecule crystal structures so we need to seek the answers elsewhere!