Wavefunction has a post about this paper from J. Med. Chem. on a series of possible antitrypanosomals from the Broad Institute's compound collection. It's a good illustration of the power of internal hydrogen bonds - in this case, one series of isomers can make the bond, but that ties up their polar groups, making them less soluble but more cell-permeable. The isomer that doesn't form the internal H-bond is more polar and more soluble, but less able to get into cells. Edit - fixed this part.
So if your compound has too many polar functionalities, an internal hydrogen bond can be just the thing to bring on better activity, because it tones things down a bit. And there are always the conformational effects to keep in mind. Tying a molecule up like that is the same as any other ring-forming gambit in medicinal chemistry: death or glory. Rarely is a strong conformational restriction silent in the SAR - usually, you either hit the magic conformer, or you move it forever out of reach.
I particularly noticed Wavefunction's line near the close of his post: "If nothing else they provide a few more valuable data points on the way to prediction nirvana.". I know what he's talking about, and I think he's far from the only computational chemist with eschatological leanings. Eventually, you'd think, we'd understand enough about all the things we're trying to model for the models to, well, work. And yes, I know that there are models that work right now, but you don't know that they're going to work until you've messed with them a while, and there are other models that don't work but look equally plausible at first, etc., and very much etc. "Prediction nirvana" would be the state where you have an idea for a new structure, you enter it into your computational model, and it immediately tells you the right answer, every single time. In theory, I think this is a reachable state of affairs. In practice, it is not yet implemented.
And remember, people have spotted glows on that horizon before and proclaimed the imminent dawn. The late 1980s were such a time, but experiences like those tend to make people more reluctant to immanentize the eschaton, or at least not where anyone can hear. But we are learning more about enthalpic and entropic interactions, conformations, hydrogen bonds, nonpolar interactions, all those things that go into computational prediction of structure and binding interactions. And if we continue to learn more, as seems likely, won't there come a point when we've learned what we need to know? If not true computational nirvana, then surely (shrink those epsilons and deltas) as arbitrarily close an approach as we like?