The poll question, Do you Need Structure To Prosecute Fragments is closed. We had 27 votes. 6 (22%) people voted for "Absolutely. No X-ray, no fragments." 6 (22%) voted for "Nope". And the majority 55% (15/27) voted for "Yes, but I am flexible as to what structure is." So, ~80% of the people who voted (self-selection?) think you do not need a X-ray structure to move forward.
So, what kind of methods can we put in the "structure" bin that is not X-ray? I think we need to define structure to get to that first question. In my eyes (and I hope this generates some dialog in the comments), structural information is data that informs on how the ligand and target interact. In my eyes, non-structural structural information is SAR without the guessing. Typical SAR: let's walk this methyl (hopefully its a magic methyl) around this ring, then ethyl, propyl, butyl, futile. Change the ring from phenyl to pyridyl...and so on.
Epitope mapping is one well established method to establish interactions between ligand and target. I am partial to this, but I am an NMR jock. To me, this is as instructive as a crystal structure. It tell you which part of the molecule is in closest contact with the target, which aren't. It leads to imminently testable medchem hypotheses.
Hydrogen-deuterium exchange (HDX) is another method which could inform on the target side of the ligand-target interaction. HDX is most robustly performed by Mass spectrometry, but can also be done by NMR (if the protein is amenable, blah^3). Is this a robust (and SENSITIVE!!!) enough method for routine mapping of ligand-protein interactions?
I ask this out of ignorance, not out of general gadfly-ness, but what methods do those people who are "flexible to structure" use to generate non-structure structural information?