Lessons For a New Medicinal Chemist

I gave my talk at the Drew University Medicinal Chemistry course, and it got me to thinking about when I was there (1990 or 1991), and my early days in medicinal chemistry in general. There are a lot of things that have to be learned when coming out of a synthetic organic chemistry background, and a few that have to be unlearned. I’ve written about some of these in the past, but I wanted to bring together some specific examples:
1. I had to appreciate just how strange and powerful metabolizing enzymes are. I approached them from the standpoint of an organic chemist, but p450 enzymes can epoxidize benzene, and I don’t know any organic chemists that can do that too well. Ripping open piperazine rings, turning cyclohexanes into cyclohexanols – there are a lot of reactions that are common in metabolic clearance that are not, to put it lightly, part of the repetoire of synthetic organic chemistry.
2. I also had to learn a rough version of the Lipinski rules – basically, that physical properties matter, although the degree to which they matter can vary. You can’t increase molecular weight or lipophilicity forever without paying for it. Small polar molecules are handled fundamentally differently than big greasy ones in vivo. This was part of learning that there are many, many different potential fates for small molecules when dosed into a living animal.
3. Another key realization, which took a while to sink in, was that biological assays had error bars, and that this was true whether or not error bars were presented on the page or the screen. Enzyme assays were a bit fuzzy compared to the numbers I was used to as a chemist, but cell assays were fuzzier. And whole-animal numbers covered an even wider range. I had to understand that this hierarchy was the general rule, and that there was not a lot to be done about it in most cases (except, importantly, to never forget that it was there).
4. As someone mentioned in the comments here the other day, alluding to an old post of mine, I had to learn that although I’d been hearing for years that time was money, that grad school had been a poor preparation for learning how true that was. I was used to making everything that I could rather than buying it, but I had to reverse that thinking completely, since I was being paid to use my head more than my hands. (That didn’t mean that I shouldn’t use my hands, far from it – only that I should use my head first whenever feasible).
5. I also had to figure out how to use my time more efficiently. Another bad grad school habit was the working all hours of the day routine, which tended to make things stretch out. Back then, if I didn’t get that reaction set up in the afternoon, well, I was coming back that evening, so I could do it then. But if I was going to keep more regular working hours, I had to plan things out better to make the best use of my time.
6. There were several big lessons to be learned about where chemistry fit into the whole drug discovery effort. One was that if I made dirty compounds, only dirty results could be expected from them. As mentioned above, even clean submissions gave alarmingly variable results sometimes; what could be expected from compounds with large and variable impurities from prep to prep? One of my jobs was not to make things harder than they already were.
7. A second big lesson, perhaps the biggest, was that chemistry was (and is) a means to an end in drug discovery. The end, of course, is a compound that’s therapeutically useful enough that people are willing to pay money for it. Without one or more of those, you are sunk. It follows, first, that anything that does not bear on the problems of producing them has to be considered secondary – not unimportant, perhaps, but secondary to the biggest issue. Without enough compounds to sell, everything else that might look so pressing will, in fact, go away – as will you.
8. The next corollary is that while synthetic organic chemistry is a very useful way to produce such compounds, it is not necessarily the only way. Biologics are an immediate exception, of course, but there are more subtle ones. One of the trickier lessons a new medicinal chemist has to learn is that the enzymes and receptors, the cells and the rats, none of them are impressed by your chemical skills and your knowledge of the literature. They do not care if the latest compound was made by the most elegant application of the latest synthetic art, or by the nastiest low-yielding grunt reaction. What matters is how good that compound might be as a drug candidate, and the chemistry used to make it usually (and should) get in line behind many more important considerations. “Quickly”, “easily”, and “reproducibly”, in this business, roughly elbow aside the more academic chemical virtues of “complexly”, “unusually”, and “with difficulty”.