If you ever worked with both computer modelers and synthetic chemists on a given project, you know that these two breeds have little in common. My personal perspective is that of an organic chemist, so I will allow myself to make some chemistry-centric comments. Let’s face it: modelers rarely provide insights that are synthetically meaningful. But I don’t want to accuse them of not knowing what can or cannot be made. Instead, tonight is about subtleties that are intuitively clear to practitioners of synthesis and might be critical to understanding and predicting the biological activity of small molecules. Take tautomerism: there is little more foundational to organic chemistry than this concept. The question is whether or not tautomerism can be relevant to docking of small molecules into receptor sites. I have dealt with many modelers and have yet to hear their appreciation of this concept, but a fairly recent paper describing a series of DNA gyrase inhibitors by Chan and Gwynn of GlaxoSmithKline provides an insight. The authors described a range of tautomeric forms of the barbituric acid portion of their inhibitor (QPT-1) and determined the corresponding co-crystal structures. In docking experiments they evaluated eight tautomers of QPT-1 and assigned them to subtly different binding sites. A tantalizing possibility is for compounds such as QPT-1 to adopt nuanced tautomeric shapes that facilitate productive interactions with the ligand-binding pocket. I think we need to pay way more attention to tautomers, especially when it comes to omnipresent amides.