Computational Nirvana

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 goi...
Source: In the Pipeline - Category: Chemists Tags: In Silico Source Type: blogs