During our recent Journal Club, we discussed the paper “A real-World Perspective on Molecular Design” by researchers from Roche. The paper presents 10 case studies where computational methods were successfully applied to different research projects. The examples are diverse enough to cover a broad spectrum of possible approaches that one may take when doing computational study. It provides a set of guidelines, a check list of computational things you can do that are compatible with short project deadlines and that can provoke further thinking and generate new ideas. It also reminds the users that although computational methods, by their nature, provide numerical values, these should be treated as a qualitative input to an ongoing project. Somewhat surprisingly, all the studies were given in a prospective manner, which rarely is the case with published computational approaches – this in a way highlights the real life, practical use.
However, it is not clear who the article is intended for: for the method users/developers it lacks depth and for experimentalists it might be overly simplified, giving the impression that these are simple approaches that work every time and which can solve anything. But, as we well know, the road to success is paved with failure. It’s a shame these failures are rarely recorded in public literature. The authors are users/developers of the methods, so we find it surprising that they consider further development of the methods useless, “further improvements in computational methods may then have less to do with science than with good software engineering and interface design”. We think that science will benefit from improvements in computational methods and vice versa. The two are tightly interlinked: there is no good software engineering without the good underlying science. However, good science can exist without good software, but good software can surely help the science.
Unfortunately, they mentioned just cases in which protein structures and ligand properties are well known. Earlier stages of molecular design lack that sort of information and thus might need implementation of different approaches, such as computationally more expensive tools that haven’t been mentioned in this perspective.
We also found that some of the words are not always used appropriately. Looking at following sentence ‘Sulfonamides are molecular chimeras, which are found to form hydrogen bonds as well as interact with unipolar environments within proteins.‘ it seems that rather then being a hybrid chimeric molecule, sulfonamides as described in the article are more of a Dr Jekyll and Mr Hyde type of molecule which can be either one or the other rather than being a bit of both at the same time. Quite what the authors really meant by unipolar is also slightly confusing; if they mean a single magnetic or electric pole (unipolar), this seems unlikely to be a feature of many protein binding sites, at least when getting in to the interesting detail!