When one embarks on the treacherous journey in organic chemistry research, proper planning of experiments is of utmost important. Nothing is more dreadful than going from one experiment to the next while changing two different parameters at a time. If you are a chemistry professor mentoring graduate students, I am sure that you wholeheartedly agree with me and may recall cases when this happened to beginning students in your lab (for example, an attempt to concurrently change a concentration and temperature in a reaction). The core of our work is to ensure that we take a rational approach to incremental learning, which is based on looking for cause/effect correlations while focusing on one variable at a time.
The idea of incremental changes goes beyond running experiments and affects our reasoning by implying that additivity should be the guiding light in reaching sound conclusions. I will provide evidence where being too dogmatic about additivity is counterproductive. As you can see, Klebe and co-workers make an excellent point: if you modify the inhibitor on the top left with a methyl group, you will get a molecule, whose binding affinity to thermolysin is improved only marginally (2.2 kcal / mol gain). If you then modify the same starting point with a carboxylic acid, again there is nothing remarkable (1 kcal / mol gain). But if you now do both of these changes (methyl and acid) at the same time, the result is profoundly better than the starting point (6.7 kcal / mol gain). While the underlying reasons for this sort of behavior are complex, this set of examples speaks to the non-additivity of functional groups and suggests that it is wrong to think about molecules as Lego-like agglomerates of functional groups. Every molecule is in its own class and simple functional group additivity is not always a sound guiding principle. You might then ask: does this imply that the vast majority of medicinal chemistry research is misguided? I don’t know. Maybe it is.