"Semi-rational in foresight, rational in hindsight"And in fact I think that could apply to many aspects of designing drugs.
For instance, you may think, "Hey, that group seems to hydrogen bond with an NH hydrogen; let me make it more electronegative by putting a nitro group somewhere close to it. Oops! That changed the binging mode completely. Tough luck".
Or "Hmm...it seems that this part of the molecule that forms all these hydrogen bonds is similar to that other molecule in that other protein-ligand complex which shows swashbuckling picomolar activity. Why don't I modify this part of the molecule to resemble the other molecule then?...Oops! Changed the entire binding mode again."
And did I mention...the tagline actually should be "Semi-rational or irrational in foresight, almost always irrational and sometimes rational in hindsight"
And all this is only at the molecular level; I don't even have to get started on how small changes can play havoc with things like solubility, pharmakokinetics and bioavailability, and of course, the notorious tox. Chemists are long familiar with what the addition of a single methyl group can do to binding and activity. At the same time, it's curious how there in fact are so many inhibitors binding to a certain class of proteins that may differ radically in other parts, yet have a highly conserved set of atoms which consistently bind to the same part of the protein. Almost miraculously, all those changes in the other parts don't seem to affect the way those few atoms bind to the protein; the best example that comes to my mind is that almost ubiquitous set of 'hinge binding' atoms in protein kinase inhibitors that mimics the ATP motif. Of course, this makes them wildly non-selective because almost no kinase is 'unhinged', but often puts you at a good starting point in terms of potency.
The fact, we still have miles to go in understanding the subtleties of protein-ligand interaction. But we have also made a mighty fine start in understanding, among other things, subtle differences in Van der Waals interactions, desolvation and entropic penalties, bioisosterism (or the lack thereof), and most recently, the role of water in ligand binding.
It's a good day to be alive sir.